Complete bibliography at Google Scholar
2023
Méndez, Constanza; Peñaloza, Hernán F; Schultz, Bárbara M; Piña-Iturbe, Alejandro; Ríos, Mariana; Moreno-Tapia, Daniela; Pereira-Sánchez, Patricia; Leighton, Diane; Orellana, Claudia; Covarrubias, Consuelo; Gálvez, Nicolás M S; Soto, Jorge A; Duarte, Luisa F; Rivera-Pérez, Daniela; Vázquez, Yaneisi; Cabrera, Alex; Bustos, Sergio; Iturriaga, Carolina; Urzua, Marcela; Navarrete, María S; Rojas, Álvaro; Fasce, Rodrigo A; Fernández, Jorge; Mora, Judith; Ramírez, Eugenio; Gaete-Argel, Aracelly; Acevedo, Mónica; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo; Weiskopf, Daniela; Grifoni, Alba; Sette, Alessandro; Zeng, Gang; Meng, Weining; ; González-Aramundiz, José V; González, Pablo A; Abarca, Katia; Melo-González, Felipe; Bueno, Susan M; Kalergis, Alexis M
Humoral and cellular response induced by a second booster of an inactivated SARS-CoV-2 vaccine in adults Journal Article
In: EBioMedicine, vol. 91, pp. 104563, 2023, ISSN: 2352-3964.
@article{pmid37099842,
title = {Humoral and cellular response induced by a second booster of an inactivated SARS-CoV-2 vaccine in adults},
author = {Constanza Méndez and Hernán F Peñaloza and Bárbara M Schultz and Alejandro Piña-Iturbe and Mariana Ríos and Daniela Moreno-Tapia and Patricia Pereira-Sánchez and Diane Leighton and Claudia Orellana and Consuelo Covarrubias and Nicolás M S Gálvez and Jorge A Soto and Luisa F Duarte and Daniela Rivera-Pérez and Yaneisi Vázquez and Alex Cabrera and Sergio Bustos and Carolina Iturriaga and Marcela Urzua and María S Navarrete and Álvaro Rojas and Rodrigo A Fasce and Jorge Fernández and Judith Mora and Eugenio Ramírez and Aracelly Gaete-Argel and Mónica Acevedo and Fernando Valiente-Echeverría and Ricardo Soto-Rifo and Daniela Weiskopf and Alba Grifoni and Alessandro Sette and Gang Zeng and Weining Meng and and José V González-Aramundiz and Pablo A González and Katia Abarca and Felipe Melo-González and Susan M Bueno and Alexis M Kalergis},
doi = {10.1016/j.ebiom.2023.104563},
issn = {2352-3964},
year = {2023},
date = {2023-05-01},
journal = {EBioMedicine},
volume = {91},
pages = {104563},
abstract = {BACKGROUND: The Omicron variant has challenged the control of the COVID-19 pandemic due to its immuno-evasive properties. The administration of a booster dose of a SARS-CoV-2 vaccine showed positive effects in the immunogenicity against SARS-CoV-2, effect that is even enhanced after the administration of a second booster.
METHODS: During a phase-3 clinical trial, we evaluated the effect of a second booster of CoronaVac®, an inactivated vaccine administered 6 months after the first booster, in the neutralization of SARS-CoV-2 (n = 87). In parallel, cellular immunity (n = 45) was analyzed in stimulated peripheral mononuclear cells by flow cytometry and ELISPOT.
FINDINGS: Although a 2.5-fold increase in neutralization of the ancestral SARS-CoV-2 was observed after the second booster when compared with prior its administration (Geometric mean units p < 0.0001; Geometric mean titer p = 0.0002), a poor neutralization against the Omicron variant was detected. Additionally, the activation of specific CD4 T lymphocytes remained stable after the second booster and, importantly, equivalent activation of CD4 T lymphocytes against the Omicron variant and the ancestral SARS-CoV-2 were found.
INTERPRETATION: Although the neutralizing response against the Omicron variant after the second booster of CoronaVac® was slightly increased, these levels are far from those observed against the ancestral SARS-CoV-2 and could most likely fail to neutralize the virus. In contrast, a robust CD4T cell response may confer protection against the Omicron variant.
FUNDING: The Ministry of Health, Government of Chile, the Confederation of Production and Commerce, Chile and SINOVAC Biotech.NIHNIAID. The Millennium Institute on Immunology and Immunotherapy.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: The Omicron variant has challenged the control of the COVID-19 pandemic due to its immuno-evasive properties. The administration of a booster dose of a SARS-CoV-2 vaccine showed positive effects in the immunogenicity against SARS-CoV-2, effect that is even enhanced after the administration of a second booster.
METHODS: During a phase-3 clinical trial, we evaluated the effect of a second booster of CoronaVac®, an inactivated vaccine administered 6 months after the first booster, in the neutralization of SARS-CoV-2 (n = 87). In parallel, cellular immunity (n = 45) was analyzed in stimulated peripheral mononuclear cells by flow cytometry and ELISPOT.
FINDINGS: Although a 2.5-fold increase in neutralization of the ancestral SARS-CoV-2 was observed after the second booster when compared with prior its administration (Geometric mean units p < 0.0001; Geometric mean titer p = 0.0002), a poor neutralization against the Omicron variant was detected. Additionally, the activation of specific CD4 T lymphocytes remained stable after the second booster and, importantly, equivalent activation of CD4 T lymphocytes against the Omicron variant and the ancestral SARS-CoV-2 were found.
INTERPRETATION: Although the neutralizing response against the Omicron variant after the second booster of CoronaVac® was slightly increased, these levels are far from those observed against the ancestral SARS-CoV-2 and could most likely fail to neutralize the virus. In contrast, a robust CD4T cell response may confer protection against the Omicron variant.
FUNDING: The Ministry of Health, Government of Chile, the Confederation of Production and Commerce, Chile and SINOVAC Biotech.NIHNIAID. The Millennium Institute on Immunology and Immunotherapy. Acevedo, Johanna; Acevedo, Mónica L; Gaete-Argel, Aracelly; Araos, Rafael; Gonzalez, Cecilia; Espinoza, Daniela; Rivas, Solange; Pizarro, Pablo; Jarpa, Stephan; Soto-Rifo, Ricardo; Jara, Alejandro; Valiente-Echeverría, Fernando
Neutralizing antibodies induced by homologous and heterologous boosters in CoronaVac vaccines in Chile Journal Article
In: Clin Microbiol Infect, vol. 29, no. 4, pp. 541.e1–541.e7, 2023, ISSN: 1469-0691.
@article{pmid36436704,
title = {Neutralizing antibodies induced by homologous and heterologous boosters in CoronaVac vaccines in Chile},
author = {Johanna Acevedo and Mónica L Acevedo and Aracelly Gaete-Argel and Rafael Araos and Cecilia Gonzalez and Daniela Espinoza and Solange Rivas and Pablo Pizarro and Stephan Jarpa and Ricardo Soto-Rifo and Alejandro Jara and Fernando Valiente-Echeverría},
doi = {10.1016/j.cmi.2022.11.017},
issn = {1469-0691},
year = {2023},
date = {2023-04-01},
journal = {Clin Microbiol Infect},
volume = {29},
number = {4},
pages = {541.e1--541.e7},
abstract = {OBJECTIVES: To determine the impact of a booster dose on the humoral response in individuals inoculated with a complete schedule of any SARS-CoV-2 vaccine, we evaluated the neutralizing antibody (NAb) titres of homologous or heterologous booster doses over a 90-days period in CoronaVac vaccinees from 3 centres in Santiago, Chile.
METHODS: Individuals previously inoculated with 2 doses of CoronaVac (N = 523) were recruited in the context of the REFUERZO clinical trial (NCT04992182) and received either placebo (N = 129), or a booster dose of CoronaVac (N = 134), BNT162b2 (N = 133), or ChAdOx1 (N = 127). Pseudovirus neutralizing antibody titres (pVNT) were determined at baseline (day 0) as well as at days 14, 30, 60, and 90 after booster dose administration.
RESULTS: Inoculating a booster dose increases the pVNTs titres at days 14 and 30 in all groups, (13.5- and 12.0-fold increase for the CoronaVac group; 247.0- and 212.3-fold increase for the BTN162b2 group; and 89.1- and 128.1-fold increase for ChAdOx1 at each time point, respectively) with a decline observed at days 60 and 90. However, although pVNTs remained significantly higher for the BTN162b2 and ChAdOx1 groups at days 60 and 90, NAb titres reached baseline levels in the CoronaVac group at 90 days after inoculation.
DISCUSSION: A single heterologous booster (BTN162b2 or ChAdOx1) in individuals who completed the CoronaVac primary series resulted in an important increase in NAb titres remaining significantly higher at least for 90 days. These data may directly impact middle- and low-income countries currently using CoronaVac as the main vaccination strategy.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
OBJECTIVES: To determine the impact of a booster dose on the humoral response in individuals inoculated with a complete schedule of any SARS-CoV-2 vaccine, we evaluated the neutralizing antibody (NAb) titres of homologous or heterologous booster doses over a 90-days period in CoronaVac vaccinees from 3 centres in Santiago, Chile.
METHODS: Individuals previously inoculated with 2 doses of CoronaVac (N = 523) were recruited in the context of the REFUERZO clinical trial (NCT04992182) and received either placebo (N = 129), or a booster dose of CoronaVac (N = 134), BNT162b2 (N = 133), or ChAdOx1 (N = 127). Pseudovirus neutralizing antibody titres (pVNT) were determined at baseline (day 0) as well as at days 14, 30, 60, and 90 after booster dose administration.
RESULTS: Inoculating a booster dose increases the pVNTs titres at days 14 and 30 in all groups, (13.5- and 12.0-fold increase for the CoronaVac group; 247.0- and 212.3-fold increase for the BTN162b2 group; and 89.1- and 128.1-fold increase for ChAdOx1 at each time point, respectively) with a decline observed at days 60 and 90. However, although pVNTs remained significantly higher for the BTN162b2 and ChAdOx1 groups at days 60 and 90, NAb titres reached baseline levels in the CoronaVac group at 90 days after inoculation.
DISCUSSION: A single heterologous booster (BTN162b2 or ChAdOx1) in individuals who completed the CoronaVac primary series resulted in an important increase in NAb titres remaining significantly higher at least for 90 days. These data may directly impact middle- and low-income countries currently using CoronaVac as the main vaccination strategy. Sauré, Denis; O'Ryan, Miguel; Torres, Juan Pablo; Zuñiga, Marcela; Soto-Rifo, Ricardo; Valiente-Echeverría, Fernando; Gaete-Argel, Aracelly; Neira, Ignasi; Saavedra, Vicente; Acevedo, Mónica L; Archila, Carmen; Acuña, Fernando; Rain, Manuel; Basso, Leonardo J
In: Lancet Microbe, vol. 4, no. 3, pp. e149–e158, 2023, ISSN: 2666-5247.
@article{pmid36716754,
title = {COVID-19 lateral flow IgG seropositivity and serum neutralising antibody responses after primary and booster vaccinations in Chile: a cross-sectional study},
author = {Denis Sauré and Miguel O'Ryan and Juan Pablo Torres and Marcela Zuñiga and Ricardo Soto-Rifo and Fernando Valiente-Echeverría and Aracelly Gaete-Argel and Ignasi Neira and Vicente Saavedra and Mónica L Acevedo and Carmen Archila and Fernando Acuña and Manuel Rain and Leonardo J Basso},
doi = {10.1016/S2666-5247(22)00290-7},
issn = {2666-5247},
year = {2023},
date = {2023-03-01},
journal = {Lancet Microbe},
volume = {4},
number = {3},
pages = {e149--e158},
abstract = {BACKGROUND: By June 30, 2022, 92·6% of the Chilean population older than 18 years had received a full primary SARS-CoV-2 vaccine series, mostly with CoronaVac (Sinovac Biotech), and 78·4% had received a booster dose, mostly heterologous with BNT162b2 (Pfizer-BioNTech) and ChAdOx1 (AstraZeneca). We previously reported national seroprevalence data from lateral flow testing of IgG SARS-CoV-2 antibodies up to 16 weeks after primary vaccination. Our aim here was to study IgG seropositivity dynamics up to 30 weeks after primary vaccination and, in CoronaVac recipients, up to 26 weeks after booster vaccination, and to establish the correlation between lateral flow tests and neutralising antibody titres.
METHODS: In this cross-sectional study, testing stations for SARS-CoV-2 IgG detection were selected and installed from March 12, 2021, in hotspots in 24 large Chilean cities, and were maintained until March 31, 2022. Individuals voluntarily approaching the testing stations were invited to perform a rapid lateral flow test via a finger prick and complete a questionnaire. Between Aug 12, 2021, and April 1, 2022, volunteers seeking medical care in the Mutual de Seguridad de la Cámara Chilena de la Construcción provided blood samples for lateral flow testing and neutralising antibody studies; inclusion criteria were age at least 18 years, history of complete primary vaccination series with CoronaVac, BNT162b2, or ChAdOx1, or no vaccine, and no previous COVID-19 diagnosis. We tested the difference in IgG positivity across time, and between primary and booster doses, in all eligible participants with complete records, controlling for age, gender, and comorbidities. We also assessed the predictive power of neutralising antibody titres and sociodemographic characteristics on the probability of IgG positive results using multivariable logistic regression.
FINDINGS: Of 107 220 individuals recruited at the testing stations, 101 070 were included in our analysis (59 862 [59·2%] women and 41 208 [40·8%] men). 65 902 (65·2%) received primary vaccination series with CoronaVac, 18 548 (18·4%) with BNT162b2, and 606 (0·6%) with ChAdOx1, and 16 014 (15·8%) received no vaccine. Among the 61 767 individuals with a complete primary vaccination series with CoronaVac, 608 (1·0%) received a CoronaVac booster, 10 095 (16·3%) received a BNT162b2 booster, and 5435 (8·8%) received a ChAdOx1 booster. After ChAdOx1 primary vaccination, seropositivity peaked at week 5 after the second dose, occurring in 13 (92·9%, 95% CI 79·4-100·0) of 14 individuals. In participants who received a complete CoronaVac primary series, the decline in seropositivity stabilised at week 18 after the second dose (86 [44·7%, 95% CI 41·8-47·7] of 1087 individuals), whereas after receiving BNT162b2, seropositivity declined slightly by week 25 after the second dose (161 [94·2%, 90·6-97·7] of 171). A lower proportion of individuals who received the CoronaVac primary series and a homologous booster were seropositive (279 [85·6%, 95% CI 81·8-89·4] of 326) by weeks 2-18 than those who received a BNT162b2 booster (7031 [98·6%, 98·4-98·9] of 7128) or a ChAdOx1 booster (2893 [98·0%, 97·5-98·5] of 2953). The correlation between IgG positivity and log of the infectious dose in 50% of neutralising antibodies was moderate, with a sensitivity of 81·4% (95% CI 76·3-86·6) and specificity of 92·5% (73·3-100·0).
INTERPRETATION: Dynamic monitoring of IgG positivity to SARS-CoV-2 can characterise antibody waning over time in the absence or presence of booster doses, providing relevant data for the design of vaccination strategies. The correlation between lateral flow test IgG titres and neutralising antibody concentrations suggests that they could be a quick and effective surveillance tool to measure protection against SARS-CoV-2.
FUNDING: Instituto Sistemas Complejos de Ingeniería, Subsecretaría de Redes Asistenciales, Ministry of Health, Chile, and Mutual de Seguridad de la Cámara Chilena de la Construcción.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: By June 30, 2022, 92·6% of the Chilean population older than 18 years had received a full primary SARS-CoV-2 vaccine series, mostly with CoronaVac (Sinovac Biotech), and 78·4% had received a booster dose, mostly heterologous with BNT162b2 (Pfizer-BioNTech) and ChAdOx1 (AstraZeneca). We previously reported national seroprevalence data from lateral flow testing of IgG SARS-CoV-2 antibodies up to 16 weeks after primary vaccination. Our aim here was to study IgG seropositivity dynamics up to 30 weeks after primary vaccination and, in CoronaVac recipients, up to 26 weeks after booster vaccination, and to establish the correlation between lateral flow tests and neutralising antibody titres.
METHODS: In this cross-sectional study, testing stations for SARS-CoV-2 IgG detection were selected and installed from March 12, 2021, in hotspots in 24 large Chilean cities, and were maintained until March 31, 2022. Individuals voluntarily approaching the testing stations were invited to perform a rapid lateral flow test via a finger prick and complete a questionnaire. Between Aug 12, 2021, and April 1, 2022, volunteers seeking medical care in the Mutual de Seguridad de la Cámara Chilena de la Construcción provided blood samples for lateral flow testing and neutralising antibody studies; inclusion criteria were age at least 18 years, history of complete primary vaccination series with CoronaVac, BNT162b2, or ChAdOx1, or no vaccine, and no previous COVID-19 diagnosis. We tested the difference in IgG positivity across time, and between primary and booster doses, in all eligible participants with complete records, controlling for age, gender, and comorbidities. We also assessed the predictive power of neutralising antibody titres and sociodemographic characteristics on the probability of IgG positive results using multivariable logistic regression.
FINDINGS: Of 107 220 individuals recruited at the testing stations, 101 070 were included in our analysis (59 862 [59·2%] women and 41 208 [40·8%] men). 65 902 (65·2%) received primary vaccination series with CoronaVac, 18 548 (18·4%) with BNT162b2, and 606 (0·6%) with ChAdOx1, and 16 014 (15·8%) received no vaccine. Among the 61 767 individuals with a complete primary vaccination series with CoronaVac, 608 (1·0%) received a CoronaVac booster, 10 095 (16·3%) received a BNT162b2 booster, and 5435 (8·8%) received a ChAdOx1 booster. After ChAdOx1 primary vaccination, seropositivity peaked at week 5 after the second dose, occurring in 13 (92·9%, 95% CI 79·4-100·0) of 14 individuals. In participants who received a complete CoronaVac primary series, the decline in seropositivity stabilised at week 18 after the second dose (86 [44·7%, 95% CI 41·8-47·7] of 1087 individuals), whereas after receiving BNT162b2, seropositivity declined slightly by week 25 after the second dose (161 [94·2%, 90·6-97·7] of 171). A lower proportion of individuals who received the CoronaVac primary series and a homologous booster were seropositive (279 [85·6%, 95% CI 81·8-89·4] of 326) by weeks 2-18 than those who received a BNT162b2 booster (7031 [98·6%, 98·4-98·9] of 7128) or a ChAdOx1 booster (2893 [98·0%, 97·5-98·5] of 2953). The correlation between IgG positivity and log of the infectious dose in 50% of neutralising antibodies was moderate, with a sensitivity of 81·4% (95% CI 76·3-86·6) and specificity of 92·5% (73·3-100·0).
INTERPRETATION: Dynamic monitoring of IgG positivity to SARS-CoV-2 can characterise antibody waning over time in the absence or presence of booster doses, providing relevant data for the design of vaccination strategies. The correlation between lateral flow test IgG titres and neutralising antibody concentrations suggests that they could be a quick and effective surveillance tool to measure protection against SARS-CoV-2.
FUNDING: Instituto Sistemas Complejos de Ingeniería, Subsecretaría de Redes Asistenciales, Ministry of Health, Chile, and Mutual de Seguridad de la Cámara Chilena de la Construcción. Acevedo, Mónica L; Gaete-Argel, Aracelly; Alonso-Palomares, Luis; de Oca, Marco Montes; Bustamante, Andrés; Gaggero, Aldo; Paredes, Fabio; Cortes, Claudia P; Pantano, Sergio; Martínez-Valdebenito, Constanza; Angulo, Jenniffer; Corre, Nicole Le; Ferrés, Marcela; Navarrete, Marcelo A; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo
2023.
@{pmid36658398,
title = {Author Correction: Differential neutralizing antibody responses elicited by CoronaVac and BNT162b2 against SARS-CoV-2 Lambda in Chile},
author = {Mónica L Acevedo and Aracelly Gaete-Argel and Luis Alonso-Palomares and Marco Montes de Oca and Andrés Bustamante and Aldo Gaggero and Fabio Paredes and Claudia P Cortes and Sergio Pantano and Constanza Martínez-Valdebenito and Jenniffer Angulo and Nicole Le Corre and Marcela Ferrés and Marcelo A Navarrete and Fernando Valiente-Echeverría and Ricardo Soto-Rifo},
doi = {10.1038/s41564-023-01324-y},
issn = {2058-5276},
year = {2023},
date = {2023-02-01},
journal = {Nat Microbiol},
volume = {8},
number = {2},
pages = {360},
keywords = {},
pubstate = {published},
tppubtype = {}
}
Gaete-Argel, Aracelly; Saavedra-Alarcón, Vicente; Sauré, Denis; Alonso-Palomares, Luis; Acevedo, Mónica L; Alarcón, Marion; Bueno, Susan M; Kalergis, Alexis M; Soto-Rifo, Ricardo; Valiente-Echeverría, Fernando; Cortes, Claudia P
Impact of homologous and heterologous boosters in neutralizing antibodies titers against SARS-CoV-2 Omicron in solid-organ transplant recipients Journal Article
In: Front Immunol, vol. 14, pp. 1135478, 2023, ISSN: 1664-3224.
@article{pmid36999018,
title = {Impact of homologous and heterologous boosters in neutralizing antibodies titers against SARS-CoV-2 Omicron in solid-organ transplant recipients},
author = {Aracelly Gaete-Argel and Vicente Saavedra-Alarcón and Denis Sauré and Luis Alonso-Palomares and Mónica L Acevedo and Marion Alarcón and Susan M Bueno and Alexis M Kalergis and Ricardo Soto-Rifo and Fernando Valiente-Echeverría and Claudia P Cortes},
doi = {10.3389/fimmu.2023.1135478},
issn = {1664-3224},
year = {2023},
date = {2023-01-01},
journal = {Front Immunol},
volume = {14},
pages = {1135478},
abstract = {INTRODUCTION: Booster doses of SARS-CoV-2 vaccines improve seroconversion rates in solid organ transplant recipients (SOTRs) but the impact of homologous and heterologous booster doses in neutralizing antibody (NAb) titers and their ability to interfere with the variant of concern Omicron are not well studied.
METHODS: We designed a prospective, open-label, observational clinical cohort study. 45 participants received two doses of BNT162b2 or CoronaVac (21-day or 28-day intervals, respectively) followed by a first and second booster with BNT162b2 (5-month apart each) and we analyzed the neutralizing antibody titers against SARSCoV-2 D614G (B.1 lineage) and Omicron (BA.1 lineage).
RESULTS: Our results show that SOTRs receiving an initial two-dose scheme of CoronaVac or BNT162b2 generate lower NAbs titers against the ancestral variant of SARS-CoV-2 when compared with healthy controls. Although these NAb titers were further decreased against the SARS-CoV-2 Omicron, a single BNT162b2 booster in both groups was sufficient to increase NAb titers against the variant of concern. More importantly, this effect was only observed in those participants responding to the first two shots but not in those not responding to the initial vaccination scheme.
DISCUSSION: The data provided here demonstrate the importance of monitoring antibody responses in immunocompromised subjects when planning booster vaccination programs in this risk group.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
INTRODUCTION: Booster doses of SARS-CoV-2 vaccines improve seroconversion rates in solid organ transplant recipients (SOTRs) but the impact of homologous and heterologous booster doses in neutralizing antibody (NAb) titers and their ability to interfere with the variant of concern Omicron are not well studied.
METHODS: We designed a prospective, open-label, observational clinical cohort study. 45 participants received two doses of BNT162b2 or CoronaVac (21-day or 28-day intervals, respectively) followed by a first and second booster with BNT162b2 (5-month apart each) and we analyzed the neutralizing antibody titers against SARSCoV-2 D614G (B.1 lineage) and Omicron (BA.1 lineage).
RESULTS: Our results show that SOTRs receiving an initial two-dose scheme of CoronaVac or BNT162b2 generate lower NAbs titers against the ancestral variant of SARS-CoV-2 when compared with healthy controls. Although these NAb titers were further decreased against the SARS-CoV-2 Omicron, a single BNT162b2 booster in both groups was sufficient to increase NAb titers against the variant of concern. More importantly, this effect was only observed in those participants responding to the first two shots but not in those not responding to the initial vaccination scheme.
DISCUSSION: The data provided here demonstrate the importance of monitoring antibody responses in immunocompromised subjects when planning booster vaccination programs in this risk group.2022
Soto, Jorge A; Melo-González, Felipe; Gutierrez-Vera, Cristián; Schultz, Bárbara M; Berríos-Rojas, Roslye V; Rivera-Pérez, Daniela; Piña-Iturbe, Alejandro; Hoppe-Elsholz, Guillermo; Duarte, Luisa F; Vázquez, Yaneisi; Moreno-Tapia, Daniela; Ríos, Mariana; Palacios, Pablo A; Garcia-Betancourt, Richard; Santibañez, Álvaro; Pacheco, Gaspar A; Mendez, Constanza; Andrade, Catalina A; Silva, Pedro H; Diethelm-Varela, Benjamín; Astudillo, Patricio; Calvo, Mario; Cárdenas, Antonio; González, Marcela; Goldsack, Macarena; Gutiérrez, Valentina; Potin, Marcela; Schilling, Andrea; Tapia, Lorena I; Twele, Loreto; Villena, Rodolfo; Grifoni, Alba; Sette, Alessandro; Weiskopf, Daniela; Fasce, Rodrigo A; Fernández, Jorge; Mora, Judith; Ramírez, Eugenio; Gaete-Argel, Aracelly; Acevedo, Mónica L; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo; Retamal-Díaz, Angello; Muñoz-Jofré, Nathalia; ; Meng, Xing; Xin, Qianqian; Alarcón-Bustamante, Eduardo; González-Aramundiz, José V; Corre, Nicole Le; Álvarez-Figueroa, María Javiera; González, Pablo A; Abarca, Katia; Perret, Cecilia; Carreño, Leandro J; Bueno, Susan M; Kalergis, Alexis M
Inactivated Vaccine-Induced SARS-CoV-2 Variant-Specific Immunity in Children Journal Article
In: mBio, vol. 13, no. 6, pp. e0131122, 2022, ISSN: 2150-7511.
@article{pmid36383021,
title = {Inactivated Vaccine-Induced SARS-CoV-2 Variant-Specific Immunity in Children},
author = {Jorge A Soto and Felipe Melo-González and Cristián Gutierrez-Vera and Bárbara M Schultz and Roslye V Berríos-Rojas and Daniela Rivera-Pérez and Alejandro Piña-Iturbe and Guillermo Hoppe-Elsholz and Luisa F Duarte and Yaneisi Vázquez and Daniela Moreno-Tapia and Mariana Ríos and Pablo A Palacios and Richard Garcia-Betancourt and Álvaro Santibañez and Gaspar A Pacheco and Constanza Mendez and Catalina A Andrade and Pedro H Silva and Benjamín Diethelm-Varela and Patricio Astudillo and Mario Calvo and Antonio Cárdenas and Marcela González and Macarena Goldsack and Valentina Gutiérrez and Marcela Potin and Andrea Schilling and Lorena I Tapia and Loreto Twele and Rodolfo Villena and Alba Grifoni and Alessandro Sette and Daniela Weiskopf and Rodrigo A Fasce and Jorge Fernández and Judith Mora and Eugenio Ramírez and Aracelly Gaete-Argel and Mónica L Acevedo and Fernando Valiente-Echeverría and Ricardo Soto-Rifo and Angello Retamal-Díaz and Nathalia Muñoz-Jofré and and Xing Meng and Qianqian Xin and Eduardo Alarcón-Bustamante and José V González-Aramundiz and Nicole Le Corre and María Javiera Álvarez-Figueroa and Pablo A González and Katia Abarca and Cecilia Perret and Leandro J Carreño and Susan M Bueno and Alexis M Kalergis},
doi = {10.1128/mbio.01311-22},
issn = {2150-7511},
year = {2022},
date = {2022-12-01},
journal = {mBio},
volume = {13},
number = {6},
pages = {e0131122},
abstract = {Multiple vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been evaluated in clinical trials. However, trials addressing the immune response in the pediatric population are scarce. The inactivated vaccine CoronaVac has been shown to be safe and immunogenic in a phase 1/2 clinical trial in a pediatric cohort in China. Here, we report interim safety and immunogenicity results of a phase 3 clinical trial for CoronaVac in healthy children and adolescents in Chile. Participants 3 to 17 years old received two doses of CoronaVac in a 4-week interval until 31 December 2021. Local and systemic adverse reactions were registered for volunteers who received one or two doses of CoronaVac. Whole-blood samples were collected from a subgroup of 148 participants for humoral and cellular immunity analyses. The main adverse reaction reported after the first and second doses was pain at the injection site. Four weeks after the second dose, an increase in neutralizing antibody titer was observed in subjects relative to their baseline visit. Similar results were found for activation of specific CD4 T cells. Neutralizing antibodies were identified against the Delta and Omicron variants. However, these titers were lower than those for the D614G strain. Importantly, comparable CD4 T cell responses were detected against these variants of concern. Therefore, CoronaVac is safe and immunogenic in subjects 3 to 17 years old, inducing neutralizing antibody secretion and activating CD4 T cells against SARS-CoV-2 and its variants. (This study has been registered at ClinicalTrials.gov under no. NCT04992260.) This work evaluated the immune response induced by two doses of CoronaVac separated by 4 weeks in healthy children and adolescents in Chile. To date, few studies have described the effects of CoronaVac in the pediatric population. Therefore, it is essential to generate knowledge regarding the protection of vaccines in this population. Along these lines, we reported the anti-S humoral response and cellular immune response to several SARS-CoV-2 proteins that have been published and recently studied. Here, we show that a vaccination schedule consisting of two doses separated by 4 weeks induces the secretion of neutralizing antibodies against SARS-CoV-2. Furthermore, CoronaVac induces the activation of CD4 T cells upon stimulation with peptides from the proteome of SARS-CoV-2. These results indicate that, even though the neutralizing antibody response induced by vaccination decreases against the Delta and Omicron variants, the cellular response against these variants is comparable to the response against the ancestral strain D614G, even being significantly higher against Omicron.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Multiple vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been evaluated in clinical trials. However, trials addressing the immune response in the pediatric population are scarce. The inactivated vaccine CoronaVac has been shown to be safe and immunogenic in a phase 1/2 clinical trial in a pediatric cohort in China. Here, we report interim safety and immunogenicity results of a phase 3 clinical trial for CoronaVac in healthy children and adolescents in Chile. Participants 3 to 17 years old received two doses of CoronaVac in a 4-week interval until 31 December 2021. Local and systemic adverse reactions were registered for volunteers who received one or two doses of CoronaVac. Whole-blood samples were collected from a subgroup of 148 participants for humoral and cellular immunity analyses. The main adverse reaction reported after the first and second doses was pain at the injection site. Four weeks after the second dose, an increase in neutralizing antibody titer was observed in subjects relative to their baseline visit. Similar results were found for activation of specific CD4 T cells. Neutralizing antibodies were identified against the Delta and Omicron variants. However, these titers were lower than those for the D614G strain. Importantly, comparable CD4 T cell responses were detected against these variants of concern. Therefore, CoronaVac is safe and immunogenic in subjects 3 to 17 years old, inducing neutralizing antibody secretion and activating CD4 T cells against SARS-CoV-2 and its variants. (This study has been registered at ClinicalTrials.gov under no. NCT04992260.) This work evaluated the immune response induced by two doses of CoronaVac separated by 4 weeks in healthy children and adolescents in Chile. To date, few studies have described the effects of CoronaVac in the pediatric population. Therefore, it is essential to generate knowledge regarding the protection of vaccines in this population. Along these lines, we reported the anti-S humoral response and cellular immune response to several SARS-CoV-2 proteins that have been published and recently studied. Here, we show that a vaccination schedule consisting of two doses separated by 4 weeks induces the secretion of neutralizing antibodies against SARS-CoV-2. Furthermore, CoronaVac induces the activation of CD4 T cells upon stimulation with peptides from the proteome of SARS-CoV-2. These results indicate that, even though the neutralizing antibody response induced by vaccination decreases against the Delta and Omicron variants, the cellular response against these variants is comparable to the response against the ancestral strain D614G, even being significantly higher against Omicron. Gálvez, Nicolás M S; Pacheco, Gaspar A; Schultz, Bárbara M; Melo-González, Felipe; Soto, Jorge A; Duarte, Luisa F; González, Liliana A; Rivera-Pérez, Daniela; Ríos, Mariana; Berrios, Roslye V; Vázquez, Yaneisi; Moreno-Tapia, Daniela; Vallejos, Omar P; Andrade, Catalina A; Hoppe-Elsholz, Guillermo; Iturriaga, Carolina; Urzua, Marcela; Navarrete, María S; Rojas, Álvaro; Fasce, Rodrigo; Fernández, Jorge; Mora, Judith; Ramírez, Eugenio; Gaete-Argel, Aracelly; Acevedo, Mónica L; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo; Weiskopf, Daniela; Grifoni, Alba; Sette, Alessandro; Zeng, Gang; Meng, Weining; ; González-Aramundiz, José V; Johnson, Marina; Goldblatt, David; González, Pablo A; Abarca, Katia; Bueno, Susan M; Kalergis, Alexis M
In: Elife, vol. 11, 2022, ISSN: 2050-084X.
@article{pmid36226829,
title = {Differences in the immune response elicited by two immunization schedules with an inactivated SARS-CoV-2 vaccine in a randomized phase 3 clinical trial},
author = {Nicolás M S Gálvez and Gaspar A Pacheco and Bárbara M Schultz and Felipe Melo-González and Jorge A Soto and Luisa F Duarte and Liliana A González and Daniela Rivera-Pérez and Mariana Ríos and Roslye V Berrios and Yaneisi Vázquez and Daniela Moreno-Tapia and Omar P Vallejos and Catalina A Andrade and Guillermo Hoppe-Elsholz and Carolina Iturriaga and Marcela Urzua and María S Navarrete and Álvaro Rojas and Rodrigo Fasce and Jorge Fernández and Judith Mora and Eugenio Ramírez and Aracelly Gaete-Argel and Mónica L Acevedo and Fernando Valiente-Echeverría and Ricardo Soto-Rifo and Daniela Weiskopf and Alba Grifoni and Alessandro Sette and Gang Zeng and Weining Meng and and José V González-Aramundiz and Marina Johnson and David Goldblatt and Pablo A González and Katia Abarca and Susan M Bueno and Alexis M Kalergis},
doi = {10.7554/eLife.81477},
issn = {2050-084X},
year = {2022},
date = {2022-10-01},
journal = {Elife},
volume = {11},
abstract = {BACKGROUND: The development of vaccines to control the coronavirus disease 2019 (COVID-19) pandemic progression is a worldwide priority. CoronaVac is an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine approved for emergency use with robust efficacy and immunogenicity data reported in trials in China, Brazil, Indonesia, Turkey, and Chile.
METHODS: This study is a randomized, multicenter, and controlled phase 3 trial in healthy Chilean adults aged ≥18 years. Volunteers received two doses of CoronaVac separated by 2 (0-14 schedule) or 4 weeks (0-28 schedule); 2302 volunteers were enrolled, 440 were part of the immunogenicity arm, and blood samples were obtained at different times. Samples from a single center are reported. Humoral immune responses were evaluated by measuring the neutralizing capacities of circulating antibodies. Cellular immune responses were assessed by ELISPOT and flow cytometry. Correlation matrixes were performed to evaluate correlations in the data measured.
RESULTS: Both schedules exhibited robust neutralizing capacities with the response induced by the 0-28 schedule being better. No differences were found in the concentration of antibodies against the virus and different variants of concern (VOCs) between schedules. Stimulation of peripheral blood mononuclear cells (PBMCs) with Mega pools of Peptides (MPs) induced the secretion of interferon (IFN)-γ and the expression of activation induced markers in CD4 T cells for both schedules. Correlation matrixes showed strong correlations between neutralizing antibodies and IFN-γ secretion.
CONCLUSIONS: Immunization with CoronaVac in Chilean adults promotes robust cellular and humoral immune responses. The 0-28 schedule induced a stronger humoral immune response than the 0-14 schedule.
FUNDING: Ministry of Health, Government of Chile, Confederation of Production and Commerce & Millennium Institute on Immunology and Immunotherapy, Chile.
CLINICAL TRIAL NUMBER: NCT04651790.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: The development of vaccines to control the coronavirus disease 2019 (COVID-19) pandemic progression is a worldwide priority. CoronaVac is an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine approved for emergency use with robust efficacy and immunogenicity data reported in trials in China, Brazil, Indonesia, Turkey, and Chile.
METHODS: This study is a randomized, multicenter, and controlled phase 3 trial in healthy Chilean adults aged ≥18 years. Volunteers received two doses of CoronaVac separated by 2 (0-14 schedule) or 4 weeks (0-28 schedule); 2302 volunteers were enrolled, 440 were part of the immunogenicity arm, and blood samples were obtained at different times. Samples from a single center are reported. Humoral immune responses were evaluated by measuring the neutralizing capacities of circulating antibodies. Cellular immune responses were assessed by ELISPOT and flow cytometry. Correlation matrixes were performed to evaluate correlations in the data measured.
RESULTS: Both schedules exhibited robust neutralizing capacities with the response induced by the 0-28 schedule being better. No differences were found in the concentration of antibodies against the virus and different variants of concern (VOCs) between schedules. Stimulation of peripheral blood mononuclear cells (PBMCs) with Mega pools of Peptides (MPs) induced the secretion of interferon (IFN)-γ and the expression of activation induced markers in CD4 T cells for both schedules. Correlation matrixes showed strong correlations between neutralizing antibodies and IFN-γ secretion.
CONCLUSIONS: Immunization with CoronaVac in Chilean adults promotes robust cellular and humoral immune responses. The 0-28 schedule induced a stronger humoral immune response than the 0-14 schedule.
FUNDING: Ministry of Health, Government of Chile, Confederation of Production and Commerce & Millennium Institute on Immunology and Immunotherapy, Chile.
CLINICAL TRIAL NUMBER: NCT04651790. Schultz, Bárbara M; Melo-González, Felipe; Duarte, Luisa F; Gálvez, Nicolás M S; Pacheco, Gaspar A; Soto, Jorge A; Berríos-Rojas, Roslye V; González, Liliana A; Moreno-Tapia, Daniela; Rivera-Pérez, Daniela; Ríos, Mariana; Vázquez, Yaneisi; Hoppe-Elsholz, Guillermo; Andrade-Parra, Catalina A; Vallejos, Omar P; Piña-Iturbe, Alejandro; Iturriaga, Carolina; Urzua, Marcela; Navarrete, María S; Rojas, Álvaro; Fasce, Rodrigo; Fernández, Jorge; Mora, Judith; Ramírez, Eugenio; Gaete-Argel, Aracelly; Acevedo, Mónica L; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo; Weiskopf, Daniela; Grifoni, Alba; Sette, Alessandro; Zeng, Gang; Meng, Weining; ; González-Aramundiz, José V; González, Pablo A; Abarca, Katia; Kalergis, Alexis M; Bueno, Susan M
A Booster Dose of CoronaVac Increases Neutralizing Antibodies and T Cells that Recognize Delta and Omicron Variants of Concern Journal Article
In: mBio, vol. 13, no. 4, pp. e0142322, 2022, ISSN: 2150-7511.
@article{pmid35946814,
title = {A Booster Dose of CoronaVac Increases Neutralizing Antibodies and T Cells that Recognize Delta and Omicron Variants of Concern},
author = {Bárbara M Schultz and Felipe Melo-González and Luisa F Duarte and Nicolás M S Gálvez and Gaspar A Pacheco and Jorge A Soto and Roslye V Berríos-Rojas and Liliana A González and Daniela Moreno-Tapia and Daniela Rivera-Pérez and Mariana Ríos and Yaneisi Vázquez and Guillermo Hoppe-Elsholz and Catalina A Andrade-Parra and Omar P Vallejos and Alejandro Piña-Iturbe and Carolina Iturriaga and Marcela Urzua and María S Navarrete and Álvaro Rojas and Rodrigo Fasce and Jorge Fernández and Judith Mora and Eugenio Ramírez and Aracelly Gaete-Argel and Mónica L Acevedo and Fernando Valiente-Echeverría and Ricardo Soto-Rifo and Daniela Weiskopf and Alba Grifoni and Alessandro Sette and Gang Zeng and Weining Meng and and José V González-Aramundiz and Pablo A González and Katia Abarca and Alexis M Kalergis and Susan M Bueno},
doi = {10.1128/mbio.01423-22},
issn = {2150-7511},
year = {2022},
date = {2022-08-01},
journal = {mBio},
volume = {13},
number = {4},
pages = {e0142322},
abstract = {CoronaVac is an inactivated SARS-CoV-2 vaccine approved by the World Health Organization (WHO). Previous studies reported increased levels of neutralizing antibodies and specific T cells 2 and 4 weeks after two doses of CoronaVac; these levels were significantly reduced at 6 to 8 months after the two doses. Here, we report the effect of a booster dose of CoronaVac on the anti-SARS-CoV-2 immune response generated against the variants of concern (VOCs), Delta and Omicron, in adults participating in a phase III clinical trial in Chile. Volunteers immunized with two doses of CoronaVac in a 4-week interval received a booster dose of the same vaccine between 24 and 30 weeks after the second dose. Neutralization capacities and T cell activation against VOCs Delta and Omicron were assessed 4 weeks after the booster dose. We observed a significant increase in neutralizing antibodies 4 weeks after the booster dose. We also observed a rise in anti-SARS-CoV-2-specific CD4 T cells over time, and these cells reached a peak 4 weeks after the booster dose. Furthermore, neutralizing antibodies and SARS-CoV-2-specific T cells induced by the booster showed activity against VOCs Delta and Omicron. Our results show that a booster dose of CoronaVac increases adults' humoral and cellular anti-SARS-CoV-2 immune responses. In addition, immunity induced by a booster dose of CoronaVac is active against VOCs, suggesting adequate protection. CoronaVac is an inactivated vaccine against SARS-CoV-2 that has been approved by WHO for emergency use. Phase III clinical trials are in progress in several countries, including China, Brazil, Turkey, and Chile, and have shown safety and immunogenicity after two doses of the vaccine. This report characterizes immune responses induced by two doses of CoronaVac followed by a booster dose 5 months after the second dose in healthy Chilean adults. The data reported here show that a booster dose increased the immune responses against SARS-CoV-2, enhancing levels of neutralizing antibodies against the ancestral strain and VOCs. Similarly, anti-SARS-CoV-2 CD4 T cell responses were increased following the booster dose. In contrast, levels of gamma interferon secretion and T cell activation against the VOCs Delta and Omicron were not significantly different from those for the ancestral strain. Therefore, a third dose of CoronaVac in a homologous vaccination schedule improves its immunogenicity in healthy volunteers.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
CoronaVac is an inactivated SARS-CoV-2 vaccine approved by the World Health Organization (WHO). Previous studies reported increased levels of neutralizing antibodies and specific T cells 2 and 4 weeks after two doses of CoronaVac; these levels were significantly reduced at 6 to 8 months after the two doses. Here, we report the effect of a booster dose of CoronaVac on the anti-SARS-CoV-2 immune response generated against the variants of concern (VOCs), Delta and Omicron, in adults participating in a phase III clinical trial in Chile. Volunteers immunized with two doses of CoronaVac in a 4-week interval received a booster dose of the same vaccine between 24 and 30 weeks after the second dose. Neutralization capacities and T cell activation against VOCs Delta and Omicron were assessed 4 weeks after the booster dose. We observed a significant increase in neutralizing antibodies 4 weeks after the booster dose. We also observed a rise in anti-SARS-CoV-2-specific CD4 T cells over time, and these cells reached a peak 4 weeks after the booster dose. Furthermore, neutralizing antibodies and SARS-CoV-2-specific T cells induced by the booster showed activity against VOCs Delta and Omicron. Our results show that a booster dose of CoronaVac increases adults' humoral and cellular anti-SARS-CoV-2 immune responses. In addition, immunity induced by a booster dose of CoronaVac is active against VOCs, suggesting adequate protection. CoronaVac is an inactivated vaccine against SARS-CoV-2 that has been approved by WHO for emergency use. Phase III clinical trials are in progress in several countries, including China, Brazil, Turkey, and Chile, and have shown safety and immunogenicity after two doses of the vaccine. This report characterizes immune responses induced by two doses of CoronaVac followed by a booster dose 5 months after the second dose in healthy Chilean adults. The data reported here show that a booster dose increased the immune responses against SARS-CoV-2, enhancing levels of neutralizing antibodies against the ancestral strain and VOCs. Similarly, anti-SARS-CoV-2 CD4 T cell responses were increased following the booster dose. In contrast, levels of gamma interferon secretion and T cell activation against the VOCs Delta and Omicron were not significantly different from those for the ancestral strain. Therefore, a third dose of CoronaVac in a homologous vaccination schedule improves its immunogenicity in healthy volunteers. Bueno, Susan M; Abarca, Katia; González, Pablo A; Gálvez, Nicolás M S; Soto, Jorge A; Duarte, Luisa F; Schultz, Bárbara M; Pacheco, Gaspar A; González, Liliana A; Vázquez, Yaneisi; Ríos, Mariana; Melo-González, Felipe; Rivera-Pérez, Daniela; Iturriaga, Carolina; Urzúa, Marcela; Domínguez, Angélica; Andrade, Catalina A; Berríos-Rojas, Roslye V; Canedo-Marroquín, Gisela; Covián, Camila; Moreno-Tapia, Daniela; Saavedra, Farides; Vallejos, Omar P; Donato, Paulina; Espinoza, Pilar; Fuentes, Daniela; González, Marcela; Guzmán, Paula; Venturelli, Paula Muñoz; Pérez, Carlos M; Potin, Marcela; Rojas, Álvaro; Fasce, Rodrigo A; Fernández, Jorge; Mora, Judith; Ramírez, Eugenio; Gaete-Argel, Aracelly; Oyarzún-Arrau, Aarón; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo; Weiskopf, Daniela; Sette, Alessandro; Zeng, Gang; Meng, Weining; González-Aramundiz, José V; Kalergis, Alexis M
Safety and Immunogenicity of an Inactivated Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine in a Subgroup of Healthy Adults in Chile Journal Article
In: Clin Infect Dis, vol. 75, no. 1, pp. e792–e804, 2022, ISSN: 1537-6591.
@article{pmid34537835,
title = {Safety and Immunogenicity of an Inactivated Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine in a Subgroup of Healthy Adults in Chile},
author = {Susan M Bueno and Katia Abarca and Pablo A González and Nicolás M S Gálvez and Jorge A Soto and Luisa F Duarte and Bárbara M Schultz and Gaspar A Pacheco and Liliana A González and Yaneisi Vázquez and Mariana Ríos and Felipe Melo-González and Daniela Rivera-Pérez and Carolina Iturriaga and Marcela Urzúa and Angélica Domínguez and Catalina A Andrade and Roslye V Berríos-Rojas and Gisela Canedo-Marroquín and Camila Covián and Daniela Moreno-Tapia and Farides Saavedra and Omar P Vallejos and Paulina Donato and Pilar Espinoza and Daniela Fuentes and Marcela González and Paula Guzmán and Paula Muñoz Venturelli and Carlos M Pérez and Marcela Potin and Álvaro Rojas and Rodrigo A Fasce and Jorge Fernández and Judith Mora and Eugenio Ramírez and Aracelly Gaete-Argel and Aarón Oyarzún-Arrau and Fernando Valiente-Echeverría and Ricardo Soto-Rifo and Daniela Weiskopf and Alessandro Sette and Gang Zeng and Weining Meng and José V González-Aramundiz and Alexis M Kalergis},
doi = {10.1093/cid/ciab823},
issn = {1537-6591},
year = {2022},
date = {2022-08-01},
journal = {Clin Infect Dis},
volume = {75},
number = {1},
pages = {e792--e804},
abstract = {BACKGROUND: The development of effective vaccines against coronavirus disease 2019 is a global priority. CoronaVac is an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine with promising safety and immunogenicity profiles. This article reports safety and immunogenicity results obtained for healthy Chilean adults aged ≥18 years in a phase 3 clinical trial.
METHODS: Volunteers randomly received 2 doses of CoronaVac or placebo, separated by 2 weeks. A total of 434 volunteers were enrolled, 397 aged 18-59 years and 37 aged ≥60 years. Solicited and unsolicited adverse reactions were registered from all volunteers. Blood samples were obtained from a subset of volunteers and analyzed for humoral and cellular measures of immunogenicity.
RESULTS: The primary adverse reaction in the 434 volunteers was pain at the injection site, with a higher incidence in the vaccine than in the placebo arm. Adverse reactions observed were mostly mild and local. No severe adverse events were reported. The humoral evaluation was performed on 81 volunteers. Seroconversion rates for specific anti-S1-receptor binding domain (RBD) immunoglobulin G (IgG) were 82.22% and 84.44% in the 18-59 year age group and 62.69% and 70.37% in the ≥60 year age group, 2 and 4 weeks after the second dose, respectively. A significant increase in circulating neutralizing antibodies was detected 2 and 4 weeks after the second dose. The cellular evaluation was performed on 47 volunteers. We detected a significant induction of T-cell responses characterized by the secretion of interferon-γ (IFN-γ) upon stimulation with Mega Pools of peptides from SARS-CoV-2.
CONCLUSIONS: Immunization with CoronaVac in a 0-14 schedule in Chilean adults aged ≥18 years is safe, induces anti-S1-RBD IgG with neutralizing capacity, activates T cells, and promotes the secretion of IFN-γ upon stimulation with SARS-CoV-2 antigens.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: The development of effective vaccines against coronavirus disease 2019 is a global priority. CoronaVac is an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine with promising safety and immunogenicity profiles. This article reports safety and immunogenicity results obtained for healthy Chilean adults aged ≥18 years in a phase 3 clinical trial.
METHODS: Volunteers randomly received 2 doses of CoronaVac or placebo, separated by 2 weeks. A total of 434 volunteers were enrolled, 397 aged 18-59 years and 37 aged ≥60 years. Solicited and unsolicited adverse reactions were registered from all volunteers. Blood samples were obtained from a subset of volunteers and analyzed for humoral and cellular measures of immunogenicity.
RESULTS: The primary adverse reaction in the 434 volunteers was pain at the injection site, with a higher incidence in the vaccine than in the placebo arm. Adverse reactions observed were mostly mild and local. No severe adverse events were reported. The humoral evaluation was performed on 81 volunteers. Seroconversion rates for specific anti-S1-receptor binding domain (RBD) immunoglobulin G (IgG) were 82.22% and 84.44% in the 18-59 year age group and 62.69% and 70.37% in the ≥60 year age group, 2 and 4 weeks after the second dose, respectively. A significant increase in circulating neutralizing antibodies was detected 2 and 4 weeks after the second dose. The cellular evaluation was performed on 47 volunteers. We detected a significant induction of T-cell responses characterized by the secretion of interferon-γ (IFN-γ) upon stimulation with Mega Pools of peptides from SARS-CoV-2.
CONCLUSIONS: Immunization with CoronaVac in a 0-14 schedule in Chilean adults aged ≥18 years is safe, induces anti-S1-RBD IgG with neutralizing capacity, activates T cells, and promotes the secretion of IFN-γ upon stimulation with SARS-CoV-2 antigens. Vargas, Leonardo; Valdivieso, Nicolás; Tempio, Fabián; Simon, Valeska; Sauma, Daniela; Valenzuela, Lucía; Beltrán, Caroll; Castillo-Delgado, Loriana; Contreras-Benavides, Ximena; Acevedo, Mónica L; Acevedo, Johanna; Gonzalez, Rafael I; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo; Rosemblatt, Mario; Lopez, Mercedes; Osorio, Fabiola; Bono, María Rosa
Serological study of CoronaVac vaccine and booster doses in Chile: immunogenicity and persistence of anti-SARS-CoV-2 spike antibodies Journal Article
In: BMC Med, vol. 20, no. 1, pp. 216, 2022, ISSN: 1741-7015.
@article{pmid35676738,
title = {Serological study of CoronaVac vaccine and booster doses in Chile: immunogenicity and persistence of anti-SARS-CoV-2 spike antibodies},
author = {Leonardo Vargas and Nicolás Valdivieso and Fabián Tempio and Valeska Simon and Daniela Sauma and Lucía Valenzuela and Caroll Beltrán and Loriana Castillo-Delgado and Ximena Contreras-Benavides and Mónica L Acevedo and Johanna Acevedo and Rafael I Gonzalez and Fernando Valiente-Echeverría and Ricardo Soto-Rifo and Mario Rosemblatt and Mercedes Lopez and Fabiola Osorio and María Rosa Bono},
doi = {10.1186/s12916-022-02406-0},
issn = {1741-7015},
year = {2022},
date = {2022-06-01},
journal = {BMC Med},
volume = {20},
number = {1},
pages = {216},
abstract = {BACKGROUND: Chile was severely affected by COVID19 outbreaks but was also one of the first countries to start a nationwide program to vaccinate against the disease. Furthermore, Chile became one of the fastest countries to inoculate a high percentage of the target population and implemented homologous and heterologous booster schemes in late 2021 to prevent potential immunological waning. The aim of this study is to compare the immunogenicity and time course of the humoral response elicited by the CoronaVac vaccine in combination with homologous versus heterologous boosters.
METHODS: We compared the immunogenicity of two doses of CoronaVac and BNT162b2 vaccines and one homologous or heterologous booster through an ELISA assay directed against the ancestral spike protein of SARS-CoV-2. Sera were collected from individuals during the vaccination schedule and throughout the implementation of homologous and heterologous booster programs in Chile.
RESULTS: Our findings demonstrate that a two-dose vaccination scheme with CoronaVac induces lower levels of anti-SARS-CoV-2 spike antibodies than BNT162b2 in a broad age range (median age 42 years; interquartile range (IQR) 27-61). Furthermore, antibody production declines with time in individuals vaccinated with CoronaVac and less noticeably, with BNT162b2. Analysis of booster schemes revealed that individuals vaccinated with two doses of CoronaVac generate immunological memory against the SARS-CoV-2 ancestral strain, which can be re-activated with homologous or heterologous (BNT162b2 and ChAdOx1) boosters. Nevertheless, the magnitude of the antibody response with the heterologous booster regime was considerably higher (induction fold BNT162b2: 11.2x; ChAdoX1; 12.4x; CoronaVac: 6.0x) than the responses induced by the homologous scheme. Both homologous and heterologous boosters induced persistent humoral responses (median 122 days, IQR (108-133)), although heterologous boosters remained superior in activating a humoral response after 100 days.
CONCLUSIONS: Two doses of CoronaVac induces antibody titers against the SARS-CoV-2 ancestral strain which are lower in magnitude than those induced by the BNT162b2 vaccine. However, the response induced by CoronaVac can be greatly potentiated with a heterologous booster scheme with BNT162b2 or ChAdOx1 vaccines. Furthermore, the heterologous and homologous booster regimes induce a durable antibody response which does not show signs of decay 3 months after the booster dose.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Chile was severely affected by COVID19 outbreaks but was also one of the first countries to start a nationwide program to vaccinate against the disease. Furthermore, Chile became one of the fastest countries to inoculate a high percentage of the target population and implemented homologous and heterologous booster schemes in late 2021 to prevent potential immunological waning. The aim of this study is to compare the immunogenicity and time course of the humoral response elicited by the CoronaVac vaccine in combination with homologous versus heterologous boosters.
METHODS: We compared the immunogenicity of two doses of CoronaVac and BNT162b2 vaccines and one homologous or heterologous booster through an ELISA assay directed against the ancestral spike protein of SARS-CoV-2. Sera were collected from individuals during the vaccination schedule and throughout the implementation of homologous and heterologous booster programs in Chile.
RESULTS: Our findings demonstrate that a two-dose vaccination scheme with CoronaVac induces lower levels of anti-SARS-CoV-2 spike antibodies than BNT162b2 in a broad age range (median age 42 years; interquartile range (IQR) 27-61). Furthermore, antibody production declines with time in individuals vaccinated with CoronaVac and less noticeably, with BNT162b2. Analysis of booster schemes revealed that individuals vaccinated with two doses of CoronaVac generate immunological memory against the SARS-CoV-2 ancestral strain, which can be re-activated with homologous or heterologous (BNT162b2 and ChAdOx1) boosters. Nevertheless, the magnitude of the antibody response with the heterologous booster regime was considerably higher (induction fold BNT162b2: 11.2x; ChAdoX1; 12.4x; CoronaVac: 6.0x) than the responses induced by the homologous scheme. Both homologous and heterologous boosters induced persistent humoral responses (median 122 days, IQR (108-133)), although heterologous boosters remained superior in activating a humoral response after 100 days.
CONCLUSIONS: Two doses of CoronaVac induces antibody titers against the SARS-CoV-2 ancestral strain which are lower in magnitude than those induced by the BNT162b2 vaccine. However, the response induced by CoronaVac can be greatly potentiated with a heterologous booster scheme with BNT162b2 or ChAdOx1 vaccines. Furthermore, the heterologous and homologous booster regimes induce a durable antibody response which does not show signs of decay 3 months after the booster dose. Acevedo, Mónica L; Gaete-Argel, Aracelly; Alonso-Palomares, Luis; de Oca, Marco Montes; Bustamante, Andrés; Gaggero, Aldo; Paredes, Fabio; Cortes, Claudia P; Pantano, Sergio; Martínez-Valdebenito, Constanza; Angulo, Jenniffer; Corre, Nicole Le; Ferrés, Marcela; Navarrete, Marcelo A; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo
2022.
@{pmid35606424,
title = {Author Correction: Differential neutralizing antibody responses elicited by CoronaVac and BNT162b2 against SARS-CoV-2 Lambda in Chile},
author = {Mónica L Acevedo and Aracelly Gaete-Argel and Luis Alonso-Palomares and Marco Montes de Oca and Andrés Bustamante and Aldo Gaggero and Fabio Paredes and Claudia P Cortes and Sergio Pantano and Constanza Martínez-Valdebenito and Jenniffer Angulo and Nicole Le Corre and Marcela Ferrés and Marcelo A Navarrete and Fernando Valiente-Echeverría and Ricardo Soto-Rifo},
doi = {10.1038/s41564-022-01154-4},
issn = {2058-5276},
year = {2022},
date = {2022-06-01},
journal = {Nat Microbiol},
volume = {7},
number = {6},
pages = {929},
keywords = {},
pubstate = {published},
tppubtype = {}
}
Wolff, Marcelo J; Acevedo, Mónica L; Núñez, María Antonieta; Lafourcade, Mónica; Gaete-Argel, Aracelly; Soto-Rifo, Ricardo; Valiente-Echeverría, Fernando
Neutralizing antibody titers elicited by CoronaVac and BNT162b2 vaccines in health care workers with and without prior SARS-CoV-2 infection Journal Article
In: J Travel Med, vol. 29, no. 3, 2022, ISSN: 1708-8305.
@article{pmid35134229,
title = {Neutralizing antibody titers elicited by CoronaVac and BNT162b2 vaccines in health care workers with and without prior SARS-CoV-2 infection},
author = {Marcelo J Wolff and Mónica L Acevedo and María Antonieta Núñez and Mónica Lafourcade and Aracelly Gaete-Argel and Ricardo Soto-Rifo and Fernando Valiente-Echeverría},
doi = {10.1093/jtm/taac010},
issn = {1708-8305},
year = {2022},
date = {2022-05-01},
journal = {J Travel Med},
volume = {29},
number = {3},
abstract = {We report neutralizing antibody titers (NAbTs) elicited by CoronaVac and BNT162b2 vaccines in healthcare workers with and without prior SARS-CoV-2 infection using both a pseudotype-based assay and a commercial kit. NAbTs were higher for the mRNA vaccine and increased in all previously infected. Good correlation between both assays was found.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
We report neutralizing antibody titers (NAbTs) elicited by CoronaVac and BNT162b2 vaccines in healthcare workers with and without prior SARS-CoV-2 infection using both a pseudotype-based assay and a commercial kit. NAbTs were higher for the mRNA vaccine and increased in all previously infected. Good correlation between both assays was found. Acevedo, Mónica L; Gaete-Argel, Aracelly; Alonso-Palomares, Luis; de Oca, Marco Montes; Bustamante, Andrés; Gaggero, Aldo; Paredes, Fabio; Cortes, Claudia P; Pantano, Sergio; Martínez-Valdebenito, Constanza; Angulo, Jenniffer; Corre, Nicole Le; Ferrés, Marcela; Navarrete, Marcelo A; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo
Differential neutralizing antibody responses elicited by CoronaVac and BNT162b2 against SARS-CoV-2 Lambda in Chile Journal Article
In: Nat Microbiol, vol. 7, no. 4, pp. 524–529, 2022, ISSN: 2058-5276.
@article{pmid35365787,
title = {Differential neutralizing antibody responses elicited by CoronaVac and BNT162b2 against SARS-CoV-2 Lambda in Chile},
author = {Mónica L Acevedo and Aracelly Gaete-Argel and Luis Alonso-Palomares and Marco Montes de Oca and Andrés Bustamante and Aldo Gaggero and Fabio Paredes and Claudia P Cortes and Sergio Pantano and Constanza Martínez-Valdebenito and Jenniffer Angulo and Nicole Le Corre and Marcela Ferrés and Marcelo A Navarrete and Fernando Valiente-Echeverría and Ricardo Soto-Rifo},
doi = {10.1038/s41564-022-01092-1},
issn = {2058-5276},
year = {2022},
date = {2022-04-01},
journal = {Nat Microbiol},
volume = {7},
number = {4},
pages = {524--529},
abstract = {SARS-CoV-2 variant Lambda was dominant in several South American countries, including Chile. To ascertain the efficacy of local vaccination efforts, we used pseudotyped viruses to characterize the neutralization capacity of antibodies elicited by CoronaVac (n = 53) and BNT162b2 (n = 56) in healthcare workers from Clínica Santa María and the Faculty of Medicine at Universidad de Chile, as well as in convalescent plasma from individuals infected during the first wave visiting the Hospital Clínico at Pontificia Universidad Católica (n = 30). We observed that BNT162b2 elicits higher neutralizing antibody titres than CoronaVac, with differences ranging from 7.4-fold for the ancestral spike (Wuhan-Hu-1) to 8.2-fold for the Lambda spike and 13-fold for the Delta spike. Compared with the ancestral virus, neutralization against D614G, Alpha, Gamma, Lambda and Delta variants was reduced by between 0.93- and 4.22-fold for CoronaVac, 1.04- and 2.38-fold for BNT162b2, and 1.26- and 2.67-fold for convalescent plasma. Comparative analyses among the spike structures of the different variants suggest that mutations in the spike protein from the Lambda variant, including the 246-252 deletion in an antigenic supersite at the N-terminal domain loop and L452Q/F490S within the receptor-binding domain, may account for immune escape. Interestingly, analyses using pseudotyped and whole viruses showed increased entry rates into HEK293T-ACE2 cells, but reduced replication rates in Vero-E6 cells for the Lambda variant when compared with the Alpha, Gamma and Delta variants. Our data show that inactivated virus and messenger RNA vaccines elicit different levels of neutralizing antibodies with different potency to neutralize SARS-CoV-2 variants, including the variant of interest Lambda.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
SARS-CoV-2 variant Lambda was dominant in several South American countries, including Chile. To ascertain the efficacy of local vaccination efforts, we used pseudotyped viruses to characterize the neutralization capacity of antibodies elicited by CoronaVac (n = 53) and BNT162b2 (n = 56) in healthcare workers from Clínica Santa María and the Faculty of Medicine at Universidad de Chile, as well as in convalescent plasma from individuals infected during the first wave visiting the Hospital Clínico at Pontificia Universidad Católica (n = 30). We observed that BNT162b2 elicits higher neutralizing antibody titres than CoronaVac, with differences ranging from 7.4-fold for the ancestral spike (Wuhan-Hu-1) to 8.2-fold for the Lambda spike and 13-fold for the Delta spike. Compared with the ancestral virus, neutralization against D614G, Alpha, Gamma, Lambda and Delta variants was reduced by between 0.93- and 4.22-fold for CoronaVac, 1.04- and 2.38-fold for BNT162b2, and 1.26- and 2.67-fold for convalescent plasma. Comparative analyses among the spike structures of the different variants suggest that mutations in the spike protein from the Lambda variant, including the 246-252 deletion in an antigenic supersite at the N-terminal domain loop and L452Q/F490S within the receptor-binding domain, may account for immune escape. Interestingly, analyses using pseudotyped and whole viruses showed increased entry rates into HEK293T-ACE2 cells, but reduced replication rates in Vero-E6 cells for the Lambda variant when compared with the Alpha, Gamma and Delta variants. Our data show that inactivated virus and messenger RNA vaccines elicit different levels of neutralizing antibodies with different potency to neutralize SARS-CoV-2 variants, including the variant of interest Lambda. González-Maldonado, Pamela; Alvarenga, Nelson; Burgos-Edwards, Alberto; Flores-Giubi, Ma Eugenia; Barúa, Javier E; Romero-Rodríguez, Ma Cristina; Soto-Rifo, Ricardo; Valiente-Echeverría, Fernando; Langjahr, Patricia; Cantero-González, Guadalupe; Sotelo, Pablo H
Screening of Natural Products Inhibitors of SARS-CoV-2 Entry Journal Article
In: Molecules, vol. 27, no. 5, 2022, ISSN: 1420-3049.
@article{pmid35268843,
title = {Screening of Natural Products Inhibitors of SARS-CoV-2 Entry},
author = {Pamela González-Maldonado and Nelson Alvarenga and Alberto Burgos-Edwards and Ma Eugenia Flores-Giubi and Javier E Barúa and Ma Cristina Romero-Rodríguez and Ricardo Soto-Rifo and Fernando Valiente-Echeverría and Patricia Langjahr and Guadalupe Cantero-González and Pablo H Sotelo},
doi = {10.3390/molecules27051743},
issn = {1420-3049},
year = {2022},
date = {2022-03-01},
journal = {Molecules},
volume = {27},
number = {5},
abstract = {The COVID-19 pandemic has led to the search for new molecules with antiviral activity against SARS-CoV-2. The entry of the virus into the cell is one of the main targets for inhibiting SARS-CoV-2 infection. Natural products are an important source of new therapeutic alternatives against diseases. Pseudotyped viruses allow the study of SARS-CoV-2 viral entry inhibitors, and due to their simplicity, they allow the screening of a large number of antiviral candidates in Biosafety Level 2 facilities. We used pseudotyped HIV-1 with the D614G SARS-CoV-2 spike glycoprotein to test its ability to infect ACE2-expressing HEK 293T cells in the presence of diverse natural products, including 21 plant extracts, 7 essential oils, and 13 compounds from plants and fungi. The 50% cytotoxic concentration (CC) was evaluated using the resazurin method. From these analyses, we determined the inhibitory activity of the extract of , which had a half-maximal inhibitory concentration (IC) of 91.65 µg/mL, a CC of 693.5 µg/mL, and a selectivity index (SI) of 7.57, indicating its potential use as an inhibitor of SARS-CoV-2 entry. Moreover, our work indicates the usefulness of the pseudotyped-virus system in the screening of SARS-CoV-2 entry inhibitors.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The COVID-19 pandemic has led to the search for new molecules with antiviral activity against SARS-CoV-2. The entry of the virus into the cell is one of the main targets for inhibiting SARS-CoV-2 infection. Natural products are an important source of new therapeutic alternatives against diseases. Pseudotyped viruses allow the study of SARS-CoV-2 viral entry inhibitors, and due to their simplicity, they allow the screening of a large number of antiviral candidates in Biosafety Level 2 facilities. We used pseudotyped HIV-1 with the D614G SARS-CoV-2 spike glycoprotein to test its ability to infect ACE2-expressing HEK 293T cells in the presence of diverse natural products, including 21 plant extracts, 7 essential oils, and 13 compounds from plants and fungi. The 50% cytotoxic concentration (CC) was evaluated using the resazurin method. From these analyses, we determined the inhibitory activity of the extract of , which had a half-maximal inhibitory concentration (IC) of 91.65 µg/mL, a CC of 693.5 µg/mL, and a selectivity index (SI) of 7.57, indicating its potential use as an inhibitor of SARS-CoV-2 entry. Moreover, our work indicates the usefulness of the pseudotyped-virus system in the screening of SARS-CoV-2 entry inhibitors. Schultz, Bárbara M; Melo-González, Felipe; Duarte, Luisa F; Gálvez, Nicolás Ms; Pacheco, Gaspar A; Soto, Jorge A; Berríos-Rojas, Roslye V; González, Liliana A; Moreno-Tapia, Daniela; Rivera-Pérez, Daniela; Ríos, Mariana; Vázquez, Yaneisi; Hoppe-Elsholz, Guillermo; Vallejos, Omar P; Iturriaga, Carolina; Urzua, Marcela; Navarrete, María S; Rojas, Álvaro; Fasce, Rodrigo; Fernández, Jorge; Mora, Judith; Ramírez, Eugenio; Gaete-Argel, Aracelly; Acevedo, Mónica; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo; Weiskopf, Daniela; Grifoni, Alba; Sette, Alessandro; Zeng, Gang; Meng, Weining; ; González-Aramundiz, José V; González, Pablo A; Abarca, Katia; Kalergis, Alexis M; Bueno, Susan M
2022.
@{pmid35441179,
title = {A booster dose of an inactivated SARS-CoV-2 vaccine increases neutralizing antibodies and T cells that recognize Delta and Omicron variants of concern},
author = {Bárbara M Schultz and Felipe Melo-González and Luisa F Duarte and Nicolás Ms Gálvez and Gaspar A Pacheco and Jorge A Soto and Roslye V Berríos-Rojas and Liliana A González and Daniela Moreno-Tapia and Daniela Rivera-Pérez and Mariana Ríos and Yaneisi Vázquez and Guillermo Hoppe-Elsholz and Omar P Vallejos and Carolina Iturriaga and Marcela Urzua and María S Navarrete and Álvaro Rojas and Rodrigo Fasce and Jorge Fernández and Judith Mora and Eugenio Ramírez and Aracelly Gaete-Argel and Mónica Acevedo and Fernando Valiente-Echeverría and Ricardo Soto-Rifo and Daniela Weiskopf and Alba Grifoni and Alessandro Sette and Gang Zeng and Weining Meng and and José V González-Aramundiz and Pablo A González and Katia Abarca and Alexis M Kalergis and Susan M Bueno},
doi = {10.1101/2021.11.16.21266350},
year = {2022},
date = {2022-02-01},
journal = {medRxiv},
abstract = {BACKGROUND: CoronaVac is an inactivated SARS-CoV-2 vaccine approved by the World Health Organization. Previous studies reported increased levels of neutralizing antibodies and specific T cells two- and four-weeks after two doses of CoronaVac , but the levels of neutralizing antibodies are reduced at six to eight months after two doses. Here we report the effect of a booster dose of CoronaVac on the anti-SARS-CoV-2 immune response generated against variants of concern (VOC) Delta and Omicron in adults participating in a phase 3 clinical trial in Chile.
METHODS: Volunteers immunized with two doses of CoronaVac in a four-week interval received a booster dose of the same vaccine between twenty-four and thirty weeks after the 2nd dose. Four weeks after the booster dose, neutralizing antibodies and T cell responses were measured. Neutralization capacities and T cell activation against VOC Delta and Omicron were detected at four weeks after the booster dose.
FINDINGS: We observed a significant increase in neutralizing antibodies at four weeks after the booster dose. We also observed an increase in CD4 T cells numbers over time, reaching a peak at four weeks after the booster dose. Furthermore, neutralizing antibodies and SARS-CoV-2 specific T cells induced by the booster showed activity against VOC Delta and Omicron.
INTERPRETATION: Our results show that a booster dose of CoronaVac increases the anti-SARS-CoV-2 humoral and cellular immune responses in adults. Immunity induced by a booster dose of CoronaVac is active against VOC, suggesting an effective protection.},
keywords = {},
pubstate = {published},
tppubtype = {}
}
BACKGROUND: CoronaVac is an inactivated SARS-CoV-2 vaccine approved by the World Health Organization. Previous studies reported increased levels of neutralizing antibodies and specific T cells two- and four-weeks after two doses of CoronaVac , but the levels of neutralizing antibodies are reduced at six to eight months after two doses. Here we report the effect of a booster dose of CoronaVac on the anti-SARS-CoV-2 immune response generated against variants of concern (VOC) Delta and Omicron in adults participating in a phase 3 clinical trial in Chile.
METHODS: Volunteers immunized with two doses of CoronaVac in a four-week interval received a booster dose of the same vaccine between twenty-four and thirty weeks after the 2nd dose. Four weeks after the booster dose, neutralizing antibodies and T cell responses were measured. Neutralization capacities and T cell activation against VOC Delta and Omicron were detected at four weeks after the booster dose.
FINDINGS: We observed a significant increase in neutralizing antibodies at four weeks after the booster dose. We also observed an increase in CD4 T cells numbers over time, reaching a peak at four weeks after the booster dose. Furthermore, neutralizing antibodies and SARS-CoV-2 specific T cells induced by the booster showed activity against VOC Delta and Omicron.
INTERPRETATION: Our results show that a booster dose of CoronaVac increases the anti-SARS-CoV-2 humoral and cellular immune responses in adults. Immunity induced by a booster dose of CoronaVac is active against VOC, suggesting an effective protection. Pereira-Montecinos, Camila; Toro-Ascuy, Daniela; Ananías-Sáez, Catarina; Gaete-Argel, Aracelly; Rojas-Fuentes, Cecilia; Riquelme-Barrios, Sebastián; Rojas-Araya, Bárbara; García-de-Gracia, Francisco; Aguilera-Cortés, Paulina; Chnaiderman, Jonás; Acevedo, Mónica L; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo
Epitranscriptomic regulation of HIV-1 full-length RNA packaging Journal Article
In: Nucleic Acids Res, vol. 50, no. 4, pp. 2302–2318, 2022, ISSN: 1362-4962.
@article{pmid35137199,
title = {Epitranscriptomic regulation of HIV-1 full-length RNA packaging},
author = {Camila Pereira-Montecinos and Daniela Toro-Ascuy and Catarina Ananías-Sáez and Aracelly Gaete-Argel and Cecilia Rojas-Fuentes and Sebastián Riquelme-Barrios and Bárbara Rojas-Araya and Francisco García-de-Gracia and Paulina Aguilera-Cortés and Jonás Chnaiderman and Mónica L Acevedo and Fernando Valiente-Echeverría and Ricardo Soto-Rifo},
doi = {10.1093/nar/gkac062},
issn = {1362-4962},
year = {2022},
date = {2022-02-01},
journal = {Nucleic Acids Res},
volume = {50},
number = {4},
pages = {2302--2318},
abstract = {During retroviral replication, the full-length RNA serves both as mRNA and genomic RNA. However, the mechanisms by which the HIV-1 Gag protein selects the two RNA molecules that will be packaged into nascent virions remain poorly understood. Here, we demonstrate that deposition of N6-methyladenosine (m6A) regulates full-length RNA packaging. While m6A deposition by METTL3/METTL14 onto the full-length RNA was associated with increased Gag synthesis and reduced packaging, FTO-mediated demethylation promoted the incorporation of the full-length RNA into viral particles. Interestingly, HIV-1 Gag associates with the RNA demethylase FTO in the nucleus and contributes to full-length RNA demethylation. We further identified two highly conserved adenosines within the 5'-UTR that have a crucial functional role in m6A methylation and packaging of the full-length RNA. Together, our data propose a novel epitranscriptomic mechanism allowing the selection of the HIV-1 full-length RNA molecules that will be used as viral genomes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
During retroviral replication, the full-length RNA serves both as mRNA and genomic RNA. However, the mechanisms by which the HIV-1 Gag protein selects the two RNA molecules that will be packaged into nascent virions remain poorly understood. Here, we demonstrate that deposition of N6-methyladenosine (m6A) regulates full-length RNA packaging. While m6A deposition by METTL3/METTL14 onto the full-length RNA was associated with increased Gag synthesis and reduced packaging, FTO-mediated demethylation promoted the incorporation of the full-length RNA into viral particles. Interestingly, HIV-1 Gag associates with the RNA demethylase FTO in the nucleus and contributes to full-length RNA demethylation. We further identified two highly conserved adenosines within the 5'-UTR that have a crucial functional role in m6A methylation and packaging of the full-length RNA. Together, our data propose a novel epitranscriptomic mechanism allowing the selection of the HIV-1 full-length RNA molecules that will be used as viral genomes. Fuentes-Villalobos, Francisco; Garrido, Jose L; Medina, Matías A; Zambrano, Nicole; Ross, Natalia; Bravo, Felipe; Gaete-Argel, Aracelly; Oyarzún-Arrau, Aarón; Amanat, Fatima; Soto-Rifo, Ricardo; Valiente-Echeverría, Fernando; Ocampo, Renato; Esveile, Christian; Ferreira, Leonila; Cabrera, Johanna; Torres, Vivianne; Rioseco, Maria L; Riquelme, Raúl; Barría, Sebastián; Alvarez, Raymond; Pinos, Yazmín; Krammer, Florian; Calvo, Mario; and, Maria I Barria
Sustained Antibody-Dependent NK Cell Functions in Mild COVID-19 Outpatients During Convalescence Journal Article
In: Front Immunol, vol. 13, pp. 796481, 2022, ISSN: 1664-3224.
@article{pmid35197972,
title = {Sustained Antibody-Dependent NK Cell Functions in Mild COVID-19 Outpatients During Convalescence},
author = {Francisco Fuentes-Villalobos and Jose L Garrido and Matías A Medina and Nicole Zambrano and Natalia Ross and Felipe Bravo and Aracelly Gaete-Argel and Aarón Oyarzún-Arrau and Fatima Amanat and Ricardo Soto-Rifo and Fernando Valiente-Echeverría and Renato Ocampo and Christian Esveile and Leonila Ferreira and Johanna Cabrera and Vivianne Torres and Maria L Rioseco and Raúl Riquelme and Sebastián Barría and Raymond Alvarez and Yazmín Pinos and Florian Krammer and Mario Calvo and Maria I Barria and },
doi = {10.3389/fimmu.2022.796481},
issn = {1664-3224},
year = {2022},
date = {2022-01-01},
journal = {Front Immunol},
volume = {13},
pages = {796481},
abstract = {The coronavirus disease 2019 (COVID19) pandemic has left researchers scrambling to identify the humoral immune correlates of protection from COVID-19. To date, the antibody mediated correlates of virus neutralization have been extensively studied. However, the extent that non-neutralizing functions contribute to anti-viral responses are ill defined. In this study, we profiled the anti-spike antibody subtype/subclass responses, along with neutralization and antibody-dependent natural killer cell functions in 83 blood samples collected between 4 and 201 days post-symptoms onset from a cohort of COVID-19 outpatients. We observed heterogeneous humoral responses against the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. Overall, anti-spike profiles were characterized by a rapid rise of IgA and sustained IgG titers. In addition, strong antibody-mediated natural killer effector responses correlated with milder disease and being female. While higher neutralization profiles were observed in males along with increased severity. These results give an insight into the underlying function of antibodies beyond neutralization and suggest that antibody-mediated natural killer cell activity is a key function of the humoral response against the SARS-CoV-2 spike protein.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The coronavirus disease 2019 (COVID19) pandemic has left researchers scrambling to identify the humoral immune correlates of protection from COVID-19. To date, the antibody mediated correlates of virus neutralization have been extensively studied. However, the extent that non-neutralizing functions contribute to anti-viral responses are ill defined. In this study, we profiled the anti-spike antibody subtype/subclass responses, along with neutralization and antibody-dependent natural killer cell functions in 83 blood samples collected between 4 and 201 days post-symptoms onset from a cohort of COVID-19 outpatients. We observed heterogeneous humoral responses against the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. Overall, anti-spike profiles were characterized by a rapid rise of IgA and sustained IgG titers. In addition, strong antibody-mediated natural killer effector responses correlated with milder disease and being female. While higher neutralization profiles were observed in males along with increased severity. These results give an insight into the underlying function of antibodies beyond neutralization and suggest that antibody-mediated natural killer cell activity is a key function of the humoral response against the SARS-CoV-2 spike protein.2021
Alonso-Palomares, Luis A; Cáceres, C Joaquín; Tapia, Rodrigo; Aguilera-Cortés, Paulina; Valenzuela, Santiago; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo; Gaggero, Aldo; Barriga, Gonzalo P
Surveillance of seasonal respiratory viruses among Chilean patients during the COVID-19 pandemic Journal Article
In: Health Sci Rep, vol. 4, no. 4, pp. e433, 2021, ISSN: 2398-8835.
@article{pmid34849406,
title = {Surveillance of seasonal respiratory viruses among Chilean patients during the COVID-19 pandemic},
author = {Luis A Alonso-Palomares and C Joaquín Cáceres and Rodrigo Tapia and Paulina Aguilera-Cortés and Santiago Valenzuela and Fernando Valiente-Echeverría and Ricardo Soto-Rifo and Aldo Gaggero and Gonzalo P Barriga},
doi = {10.1002/hsr2.433},
issn = {2398-8835},
year = {2021},
date = {2021-12-01},
journal = {Health Sci Rep},
volume = {4},
number = {4},
pages = {e433},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Pietrantoni, Gianfranco; Gaete-Argel, Aracelly; Herrera-Rojo, Diego; Ibarra-Karmy, Rodrigo; Bustos, Fernando J; Valiente-Echeverría, Fernando; Arriagada, Gloria
Dynein Light-Chain Dynlrb2 Is Essential for Murine Leukemia Virus Traffic and Nuclear Entry Journal Article
In: J Virol, vol. 95, no. 15, pp. e0017021, 2021, ISSN: 1098-5514.
@article{pmid33980598,
title = {Dynein Light-Chain Dynlrb2 Is Essential for Murine Leukemia Virus Traffic and Nuclear Entry},
author = {Gianfranco Pietrantoni and Aracelly Gaete-Argel and Diego Herrera-Rojo and Rodrigo Ibarra-Karmy and Fernando J Bustos and Fernando Valiente-Echeverría and Gloria Arriagada},
doi = {10.1128/JVI.00170-21},
issn = {1098-5514},
year = {2021},
date = {2021-07-01},
journal = {J Virol},
volume = {95},
number = {15},
pages = {e0017021},
abstract = {Murine leukemia virus (MLV) requires the infected cell to divide to access the nucleus to integrate into the host genome. It has been determined that MLV uses the microtubule and actin network to reach the nucleus at the early stages of infection. Several studies have shown that viruses use the dynein motor protein associated with microtubules for their displacement. We have previously reported that dynein light-chain roadblock type 2 (Dynlrb2) knockdown significantly decreases MLV infection compared to nonsilenced cells, suggesting a functional association between this dynein light chain and MLV preintegration complex (PIC). In this study, we aimed to determine if the dynein complex Dynlrb2 subunit plays an essential role in the retrograde transport of MLV. For this, an MLV mutant containing the green fluorescent protein (GFP) fused to the viral protein p12 was used to assay the PIC localization and speed in cells in which the expression of Dynlrb2 was modulated. We found a significant decrease in the arrival of MLV PIC to the nucleus and a reduced net speed of MLV PICs when Dynlrb2 was knocked down. In contrast, an increase in nuclear localization was observed when Dynlrb2 was overexpressed. Our results suggest that Dynlrb2 plays an essential role in MLV retrograde transport. Different viruses use different components of cytoplasmic dynein complex to traffic to their replication site. We have found that murine leukemia virus (MLV) depends on dynein light-chain Dynlrb2 for infection, retrograde traffic, and nuclear entry. Our study provides new information regarding the molecular requirements for retrograde transport of MLV preintegration complex and demonstrates the essential role of Dynlrb2 in MLV infection.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Murine leukemia virus (MLV) requires the infected cell to divide to access the nucleus to integrate into the host genome. It has been determined that MLV uses the microtubule and actin network to reach the nucleus at the early stages of infection. Several studies have shown that viruses use the dynein motor protein associated with microtubules for their displacement. We have previously reported that dynein light-chain roadblock type 2 (Dynlrb2) knockdown significantly decreases MLV infection compared to nonsilenced cells, suggesting a functional association between this dynein light chain and MLV preintegration complex (PIC). In this study, we aimed to determine if the dynein complex Dynlrb2 subunit plays an essential role in the retrograde transport of MLV. For this, an MLV mutant containing the green fluorescent protein (GFP) fused to the viral protein p12 was used to assay the PIC localization and speed in cells in which the expression of Dynlrb2 was modulated. We found a significant decrease in the arrival of MLV PIC to the nucleus and a reduced net speed of MLV PICs when Dynlrb2 was knocked down. In contrast, an increase in nuclear localization was observed when Dynlrb2 was overexpressed. Our results suggest that Dynlrb2 plays an essential role in MLV retrograde transport. Different viruses use different components of cytoplasmic dynein complex to traffic to their replication site. We have found that murine leukemia virus (MLV) depends on dynein light-chain Dynlrb2 for infection, retrograde traffic, and nuclear entry. Our study provides new information regarding the molecular requirements for retrograde transport of MLV preintegration complex and demonstrates the essential role of Dynlrb2 in MLV infection. Hernández-Díaz, Tomás; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo
RNA Helicase DDX3: A Double-Edged Sword for Viral Replication and Immune Signaling Journal Article
In: Microorganisms, vol. 9, no. 6, 2021, ISSN: 2076-2607.
@article{pmid34204859,
title = {RNA Helicase DDX3: A Double-Edged Sword for Viral Replication and Immune Signaling},
author = {Tomás Hernández-Díaz and Fernando Valiente-Echeverría and Ricardo Soto-Rifo},
doi = {10.3390/microorganisms9061206},
issn = {2076-2607},
year = {2021},
date = {2021-06-01},
journal = {Microorganisms},
volume = {9},
number = {6},
abstract = {DDX3 is a cellular ATP-dependent RNA helicase involved in different aspects of RNA metabolism ranging from transcription to translation and therefore, DDX3 participates in the regulation of key cellular processes including cell cycle progression, apoptosis, cancer and the antiviral immune response leading to type-I interferon production. DDX3 has also been described as an essential cellular factor for the replication of different viruses, including important human threats such HIV-1 or HCV, and different small molecules targeting DDX3 activity have been developed. Indeed, increasing evidence suggests that DDX3 can be considered not only a promising but also a viable target for anticancer and antiviral treatments. In this review, we summarize distinct functional aspects of DDX3 focusing on its participation as a double-edged sword in the host immune response and in the replication cycle of different viruses.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
DDX3 is a cellular ATP-dependent RNA helicase involved in different aspects of RNA metabolism ranging from transcription to translation and therefore, DDX3 participates in the regulation of key cellular processes including cell cycle progression, apoptosis, cancer and the antiviral immune response leading to type-I interferon production. DDX3 has also been described as an essential cellular factor for the replication of different viruses, including important human threats such HIV-1 or HCV, and different small molecules targeting DDX3 activity have been developed. Indeed, increasing evidence suggests that DDX3 can be considered not only a promising but also a viable target for anticancer and antiviral treatments. In this review, we summarize distinct functional aspects of DDX3 focusing on its participation as a double-edged sword in the host immune response and in the replication cycle of different viruses. Peña, Mónica; Ampuero, Manuel; Garcés, Carlos; Gaggero, Aldo; García, Patricia; Velasquez, María Soledad; Luza, Ricardo; Alvarez, Pía; Paredes, Fabio; Acevedo, Johanna; Farfán, Mauricio J; Solari, Sandra; Soto-Rifo, Ricardo; Valiente-Echeverría, Fernando
Performance of SARS-CoV-2 rapid antigen test compared with real-time RT-PCR in asymptomatic individuals Journal Article
In: Int J Infect Dis, vol. 107, pp. 201–204, 2021, ISSN: 1878-3511.
@article{pmid33945868,
title = {Performance of SARS-CoV-2 rapid antigen test compared with real-time RT-PCR in asymptomatic individuals},
author = {Mónica Peña and Manuel Ampuero and Carlos Garcés and Aldo Gaggero and Patricia García and María Soledad Velasquez and Ricardo Luza and Pía Alvarez and Fabio Paredes and Johanna Acevedo and Mauricio J Farfán and Sandra Solari and Ricardo Soto-Rifo and Fernando Valiente-Echeverría},
doi = {10.1016/j.ijid.2021.04.087},
issn = {1878-3511},
year = {2021},
date = {2021-06-01},
journal = {Int J Infect Dis},
volume = {107},
pages = {201--204},
abstract = {Screening, testing and contact tracing plays a pivotal role in control of the COVID-19 pandemic. To enable this it is necessary to increase the testing capacity. This study compared a SARS-CoV-2 rapid antigen test (RAT) and RT-PCR in 842 asymptomatic individuals from Tarapacá, Chile. A sensitivity of 69.86%, specificity of 99.61%, PPV of 94.44% and NPP of 97.22% with Ct values (Ct > 27) that were significantly higher among individuals with false-negative RAT were reported. These results support the fact that RAT might have a significant impact on the identification of asymptomatic carriers in areas that lack suitable laboratories to perform SARS-CoV-2 real-time RT-PCR diagnostics, or the results take more than 24-48 h, as well as zones with high traffic of individuals such as border/customs, airports, interregional bus, train stations or in any mass testing campaign requiring rapid results.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Screening, testing and contact tracing plays a pivotal role in control of the COVID-19 pandemic. To enable this it is necessary to increase the testing capacity. This study compared a SARS-CoV-2 rapid antigen test (RAT) and RT-PCR in 842 asymptomatic individuals from Tarapacá, Chile. A sensitivity of 69.86%, specificity of 99.61%, PPV of 94.44% and NPP of 97.22% with Ct values (Ct > 27) that were significantly higher among individuals with false-negative RAT were reported. These results support the fact that RAT might have a significant impact on the identification of asymptomatic carriers in areas that lack suitable laboratories to perform SARS-CoV-2 real-time RT-PCR diagnostics, or the results take more than 24-48 h, as well as zones with high traffic of individuals such as border/customs, airports, interregional bus, train stations or in any mass testing campaign requiring rapid results. García-de-Gracia, Francisco; Gaete-Argel, Aracelly; Riquelme-Barrios, Sebastián; Pereira-Montecinos, Camila; Rojas-Araya, Bárbara; Aguilera, Paulina; Oyarzún-Arrau, Aarón; Rojas-Fuentes, Cecilia; Acevedo, Mónica L; Chnaiderman, Jonás; Valiente-Echeverría, Fernando; Toro-Ascuy, Daniela; Soto-Rifo, Ricardo
CBP80/20-dependent translation initiation factor (CTIF) inhibits HIV-1 Gag synthesis by targeting the function of the viral protein Rev Journal Article
In: RNA Biol, vol. 18, no. 5, pp. 745–758, 2021, ISSN: 1555-8584.
@article{pmid33103564,
title = {CBP80/20-dependent translation initiation factor (CTIF) inhibits HIV-1 Gag synthesis by targeting the function of the viral protein Rev},
author = {Francisco García-de-Gracia and Aracelly Gaete-Argel and Sebastián Riquelme-Barrios and Camila Pereira-Montecinos and Bárbara Rojas-Araya and Paulina Aguilera and Aarón Oyarzún-Arrau and Cecilia Rojas-Fuentes and Mónica L Acevedo and Jonás Chnaiderman and Fernando Valiente-Echeverría and Daniela Toro-Ascuy and Ricardo Soto-Rifo},
doi = {10.1080/15476286.2020.1832375},
issn = {1555-8584},
year = {2021},
date = {2021-05-01},
journal = {RNA Biol},
volume = {18},
number = {5},
pages = {745--758},
abstract = {Translation initiation of the human immunodeficiency virus type-1 (HIV-1) full-length RNA has been shown to occur through cap-dependent and IRES-driven mechanisms. Previous studies suggested that the nuclear cap-binding complex (CBC) rather than eIF4E drives cap-dependent translation of the full-length RNA and we have recently reported that the CBC subunit CBP80 supports the function of the viral protein Rev during nuclear export and translation of this viral transcript. Ribosome recruitment during CBC-dependent translation of cellular mRNAs relies on the activity CBP80/20 translation initiation factor (CTIF), which bridges CBP80 and the 40S ribosomal subunit through interactions with eIF3g. Here, we report that CTIF inhibits HIV-1 and HIV-2 Gag synthesis from the full-length RNA. Our results indicate that CTIF associates with HIV-1 Rev through its N-terminal domain and is recruited onto the full-length RNA ribonucleoprotein complex in order to interfere with Gag synthesis. We also demonstrate that CTIF induces the cytoplasmic accumulation of Rev impeding the association of the viral protein with CBP80. We finally show that Rev interferes with the association of CTIF with CBP80 indicating that CTIF and Rev compete for the CBC subunit.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Translation initiation of the human immunodeficiency virus type-1 (HIV-1) full-length RNA has been shown to occur through cap-dependent and IRES-driven mechanisms. Previous studies suggested that the nuclear cap-binding complex (CBC) rather than eIF4E drives cap-dependent translation of the full-length RNA and we have recently reported that the CBC subunit CBP80 supports the function of the viral protein Rev during nuclear export and translation of this viral transcript. Ribosome recruitment during CBC-dependent translation of cellular mRNAs relies on the activity CBP80/20 translation initiation factor (CTIF), which bridges CBP80 and the 40S ribosomal subunit through interactions with eIF3g. Here, we report that CTIF inhibits HIV-1 and HIV-2 Gag synthesis from the full-length RNA. Our results indicate that CTIF associates with HIV-1 Rev through its N-terminal domain and is recruited onto the full-length RNA ribonucleoprotein complex in order to interfere with Gag synthesis. We also demonstrate that CTIF induces the cytoplasmic accumulation of Rev impeding the association of the viral protein with CBP80. We finally show that Rev interferes with the association of CTIF with CBP80 indicating that CTIF and Rev compete for the CBC subunit. Bueno, Susan M; Abarca, Katia; González, Pablo A; Gálvez, Nicolás Ms; Soto, Jorge A; Duarte, Luisa F; Schultz, Bárbara M; Pacheco, Gaspar A; González, Liliana A; Vázquez, Yaneisi; Ríos, Mariana; Melo-González, Felipe; Rivera-Pérez, Daniela; Iturriaga, Carolina; Urzúa, Marcela; Dominguez, Angélica; Andrade, Catalina A; Berrios, Roslye V; Canedo-Marroquín, Gisela; Covián, Camila; Moreno-Tapia, Daniela; Saavedra, Farides; Vallejos, Omar P; Donato, Paulina; Espinoza, Pilar; Fuentes, Daniela; González, Marcela; Guzmán, Paula; Muñoz-Venturelli, Paula; Pérez, Carlos M; Potin, Marcela; Rojas, Alvaro; Fasce, Rodrigo; Fernández, Jorge; Mora, Judith; Ramírez, Eugenio; Gaete-Argel, Aracelly; Oyarzún-Arrau, Aarón; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo; Weiskopf, Daniela; Sette, Alessandro; Zeng, Gang; Meng, Weining; González-Aramundiz, José V; Kalergis, Alexis M
2021.
@{pmid35441164,
title = {Interim report: Safety and immunogenicity of an inactivated vaccine against SARS-CoV-2 in healthy chilean adults in a phase 3 clinical trial},
author = {Susan M Bueno and Katia Abarca and Pablo A González and Nicolás Ms Gálvez and Jorge A Soto and Luisa F Duarte and Bárbara M Schultz and Gaspar A Pacheco and Liliana A González and Yaneisi Vázquez and Mariana Ríos and Felipe Melo-González and Daniela Rivera-Pérez and Carolina Iturriaga and Marcela Urzúa and Angélica Dominguez and Catalina A Andrade and Roslye V Berrios and Gisela Canedo-Marroquín and Camila Covián and Daniela Moreno-Tapia and Farides Saavedra and Omar P Vallejos and Paulina Donato and Pilar Espinoza and Daniela Fuentes and Marcela González and Paula Guzmán and Paula Muñoz-Venturelli and Carlos M Pérez and Marcela Potin and Alvaro Rojas and Rodrigo Fasce and Jorge Fernández and Judith Mora and Eugenio Ramírez and Aracelly Gaete-Argel and Aarón Oyarzún-Arrau and Fernando Valiente-Echeverría and Ricardo Soto-Rifo and Daniela Weiskopf and Alessandro Sette and Gang Zeng and Weining Meng and José V González-Aramundiz and Alexis M Kalergis},
doi = {10.1101/2021.03.31.21254494},
year = {2021},
date = {2021-04-01},
journal = {medRxiv},
abstract = {BACKGROUND: The ongoing COVID-19 pandemic has had a significant impact worldwide, with an incommensurable social and economic burden. The rapid development of safe and protective vaccines against this disease is a global priority. CoronaVac is a vaccine prototype based on inactivated SARS-CoV-2, which has shown promising safety and immunogenicity profiles in pre-clinical studies and phase 1/2 trials in China. To this day, four phase 3 clinical trials are ongoing with CoronaVac in Brazil, Indonesia, Turkey, and Chile. This article reports the safety and immunogenicity results obtained in a subgroup of participants aged 18 years and older enrolled in the phase 3 Clinical Trial held in Chile.
METHODS: This is a multicenter phase 3 clinical trial. Healthcare workers aged 18 years and older were randomly assigned to receive two doses of CoronaVac or placebo separated by two weeks (0-14). We report preliminary safety results obtained for a subset of 434 participants, and antibody and cell-mediated immunity results obtained in a subset of participants assigned to the immunogenicity arm. The primary and secondary aims of the study include the evaluation of safety parameters and immunogenicity against SARS-CoV-2 after immunization, respectively. This trial is registered at clinicaltrials.gov ( NCT04651790 ).
FINDINGS: The recruitment of participants occurred between November 27 , 2020, until January 9 , 2021. 434 participants were enrolled, 397 were 18-59 years old, and 37 were ≥60 years old. Of these, 270 were immunized with CoronaVac, and the remaining 164 participants were inoculated with the corresponding placebo. The primary adverse reaction was pain at the injection site, with a higher incidence in the vaccine arm (55.6%) than in the placebo arm (40.0%). Moreover, the incidence of pain at the injection site in the 18-59 years old group was 58.4% as compared to 32.0% in the ≥60 years old group. The seroconversion rate for specific anti-S1-RBD IgG was 47.8% for the 18-59 years old group 14 days post immunization (p.i.) and 95.6% 28 and 42 days p.i. For the ≥60 years old group, the seroconversion rate was 18.1%, 100%, and 87.5% at 14, 28, and 42 days p.i., respectively. Importantly, we observed a 95.7% seroconversion rate in neutralizing antibodies for the 18-59 years old group 28 and 42 days p.i. The ≥60 years old group exhibited seroconversion rates of 90.0% and 100% at 28 and 42 days p.i. Interestingly, we did not observe a significant seroconversion rate of anti-N-SARS-CoV-2 IgG for the 18-59 years old group. For the participants ≥60 years old, a modest rate of seroconversion at 42 days p.i. was observed (37.5%). We observed a significant induction of a T cell response characterized by the secretion of IFN-γ upon stimulation with Mega Pools of peptides derived from SARS-CoV-2 proteins. No significant differences between the two age groups were observed for cell-mediated immunity.
INTERPRETATION: Immunization with CoronaVac in a 0-14 schedule in adults of 18 years and older in the Chilean population is safe and induces specific IgG production against the S1-RBD with neutralizing capacity, as well as the activation of T cells secreting IFN-γ, upon recognition of SARS-CoV-2 antigens.
FUNDING: Ministry of Health of the Chilean Government; Confederation of Production and Commerce, Chile; Consortium of Universities for Vaccines and Therapies against COVID-19, Chile; Millennium Institute on Immunology and Immunotherapy.},
keywords = {},
pubstate = {published},
tppubtype = {}
}
BACKGROUND: The ongoing COVID-19 pandemic has had a significant impact worldwide, with an incommensurable social and economic burden. The rapid development of safe and protective vaccines against this disease is a global priority. CoronaVac is a vaccine prototype based on inactivated SARS-CoV-2, which has shown promising safety and immunogenicity profiles in pre-clinical studies and phase 1/2 trials in China. To this day, four phase 3 clinical trials are ongoing with CoronaVac in Brazil, Indonesia, Turkey, and Chile. This article reports the safety and immunogenicity results obtained in a subgroup of participants aged 18 years and older enrolled in the phase 3 Clinical Trial held in Chile.
METHODS: This is a multicenter phase 3 clinical trial. Healthcare workers aged 18 years and older were randomly assigned to receive two doses of CoronaVac or placebo separated by two weeks (0-14). We report preliminary safety results obtained for a subset of 434 participants, and antibody and cell-mediated immunity results obtained in a subset of participants assigned to the immunogenicity arm. The primary and secondary aims of the study include the evaluation of safety parameters and immunogenicity against SARS-CoV-2 after immunization, respectively. This trial is registered at clinicaltrials.gov ( NCT04651790 ).
FINDINGS: The recruitment of participants occurred between November 27 , 2020, until January 9 , 2021. 434 participants were enrolled, 397 were 18-59 years old, and 37 were ≥60 years old. Of these, 270 were immunized with CoronaVac, and the remaining 164 participants were inoculated with the corresponding placebo. The primary adverse reaction was pain at the injection site, with a higher incidence in the vaccine arm (55.6%) than in the placebo arm (40.0%). Moreover, the incidence of pain at the injection site in the 18-59 years old group was 58.4% as compared to 32.0% in the ≥60 years old group. The seroconversion rate for specific anti-S1-RBD IgG was 47.8% for the 18-59 years old group 14 days post immunization (p.i.) and 95.6% 28 and 42 days p.i. For the ≥60 years old group, the seroconversion rate was 18.1%, 100%, and 87.5% at 14, 28, and 42 days p.i., respectively. Importantly, we observed a 95.7% seroconversion rate in neutralizing antibodies for the 18-59 years old group 28 and 42 days p.i. The ≥60 years old group exhibited seroconversion rates of 90.0% and 100% at 28 and 42 days p.i. Interestingly, we did not observe a significant seroconversion rate of anti-N-SARS-CoV-2 IgG for the 18-59 years old group. For the participants ≥60 years old, a modest rate of seroconversion at 42 days p.i. was observed (37.5%). We observed a significant induction of a T cell response characterized by the secretion of IFN-γ upon stimulation with Mega Pools of peptides derived from SARS-CoV-2 proteins. No significant differences between the two age groups were observed for cell-mediated immunity.
INTERPRETATION: Immunization with CoronaVac in a 0-14 schedule in adults of 18 years and older in the Chilean population is safe and induces specific IgG production against the S1-RBD with neutralizing capacity, as well as the activation of T cells secreting IFN-γ, upon recognition of SARS-CoV-2 antigens.
FUNDING: Ministry of Health of the Chilean Government; Confederation of Production and Commerce, Chile; Consortium of Universities for Vaccines and Therapies against COVID-19, Chile; Millennium Institute on Immunology and Immunotherapy. Balcells, María Elvira; Rojas, Luis; Corre, Nicole Le; Martínez-Valdebenito, Constanza; Ceballos, María Elena; Ferrés, Marcela; Chang, Mayling; Vizcaya, Cecilia; Mondaca, Sebastián; Huete, Álvaro; Castro, Ricardo; Sarmiento, Mauricio; Villarroel, Luis; Pizarro, Alejandra; Ross, Patricio; Santander, Jaime; Lara, Bárbara; Ferrada, Marcela; Vargas-Salas, Sergio; Beltrán-Pavez, Carolina; Soto-Rifo, Ricardo; Valiente-Echeverría, Fernando; Caglevic, Christian; Mahave, Mauricio; Selman, Carolina; Gazitúa, Raimundo; Briones, José Luis; Villarroel-Espindola, Franz; Balmaceda, Carlos; Espinoza, Manuel A; Pereira, Jaime; Nervi, Bruno
Early versus deferred anti-SARS-CoV-2 convalescent plasma in patients admitted for COVID-19: A randomized phase II clinical trial Journal Article
In: PLoS Med, vol. 18, no. 3, pp. e1003415, 2021, ISSN: 1549-1676.
@article{pmid33657114,
title = {Early versus deferred anti-SARS-CoV-2 convalescent plasma in patients admitted for COVID-19: A randomized phase II clinical trial},
author = {María Elvira Balcells and Luis Rojas and Nicole Le Corre and Constanza Martínez-Valdebenito and María Elena Ceballos and Marcela Ferrés and Mayling Chang and Cecilia Vizcaya and Sebastián Mondaca and Álvaro Huete and Ricardo Castro and Mauricio Sarmiento and Luis Villarroel and Alejandra Pizarro and Patricio Ross and Jaime Santander and Bárbara Lara and Marcela Ferrada and Sergio Vargas-Salas and Carolina Beltrán-Pavez and Ricardo Soto-Rifo and Fernando Valiente-Echeverría and Christian Caglevic and Mauricio Mahave and Carolina Selman and Raimundo Gazitúa and José Luis Briones and Franz Villarroel-Espindola and Carlos Balmaceda and Manuel A Espinoza and Jaime Pereira and Bruno Nervi},
doi = {10.1371/journal.pmed.1003415},
issn = {1549-1676},
year = {2021},
date = {2021-03-01},
journal = {PLoS Med},
volume = {18},
number = {3},
pages = {e1003415},
abstract = {BACKGROUND: Convalescent plasma (CP), despite limited evidence on its efficacy, is being widely used as a compassionate therapy for hospitalized patients with COVID-19. We aimed to evaluate the efficacy and safety of early CP therapy in COVID-19 progression.
METHODS AND FINDINGS: The study was an open-label, single-center randomized clinical trial performed in an academic medical center in Santiago, Chile, from May 10, 2020, to July 18, 2020, with final follow-up until August 17, 2020. The trial included patients hospitalized within the first 7 days of COVID-19 symptom onset, presenting risk factors for illness progression and not on mechanical ventilation. The intervention consisted of immediate CP (early plasma group) versus no CP unless developing prespecified criteria of deterioration (deferred plasma group). Additional standard treatment was allowed in both arms. The primary outcome was a composite of mechanical ventilation, hospitalization for >14 days, or death. The key secondary outcomes included time to respiratory failure, days of mechanical ventilation, hospital length of stay, mortality at 30 days, and SARS-CoV-2 real-time PCR clearance rate. Of 58 randomized patients (mean age, 65.8 years; 50% male), 57 (98.3%) completed the trial. A total of 13 (43.3%) participants from the deferred group received plasma based on clinical aggravation. We failed to find benefit in the primary outcome (32.1% versus 33.3%, odds ratio [OR] 0.95, 95% CI 0.32-2.84, p > 0.999) in the early versus deferred CP group. The in-hospital mortality rate was 17.9% versus 6.7% (OR 3.04, 95% CI 0.54-17.17 p = 0.246), mechanical ventilation 17.9% versus 6.7% (OR 3.04, 95% CI 0.54-17.17, p = 0.246), and prolonged hospitalization 21.4% versus 30.0% (OR 0.64, 95% CI, 0.19-2.10, p = 0.554) in the early versus deferred CP group, respectively. The viral clearance rate on day 3 (26% versus 8%, p = 0.204) and day 7 (38% versus 19%, p = 0.374) did not differ between groups. Two patients experienced serious adverse events within 6 hours after plasma transfusion. The main limitation of this study is the lack of statistical power to detect a smaller but clinically relevant therapeutic effect of CP, as well as not having confirmed neutralizing antibodies in donor before plasma infusion.
CONCLUSIONS: In the present study, we failed to find evidence of benefit in mortality, length of hospitalization, or mechanical ventilation requirement by immediate addition of CP therapy in the early stages of COVID-19 compared to its use only in case of patient deterioration.
TRIAL REGISTRATION: NCT04375098.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Convalescent plasma (CP), despite limited evidence on its efficacy, is being widely used as a compassionate therapy for hospitalized patients with COVID-19. We aimed to evaluate the efficacy and safety of early CP therapy in COVID-19 progression.
METHODS AND FINDINGS: The study was an open-label, single-center randomized clinical trial performed in an academic medical center in Santiago, Chile, from May 10, 2020, to July 18, 2020, with final follow-up until August 17, 2020. The trial included patients hospitalized within the first 7 days of COVID-19 symptom onset, presenting risk factors for illness progression and not on mechanical ventilation. The intervention consisted of immediate CP (early plasma group) versus no CP unless developing prespecified criteria of deterioration (deferred plasma group). Additional standard treatment was allowed in both arms. The primary outcome was a composite of mechanical ventilation, hospitalization for >14 days, or death. The key secondary outcomes included time to respiratory failure, days of mechanical ventilation, hospital length of stay, mortality at 30 days, and SARS-CoV-2 real-time PCR clearance rate. Of 58 randomized patients (mean age, 65.8 years; 50% male), 57 (98.3%) completed the trial. A total of 13 (43.3%) participants from the deferred group received plasma based on clinical aggravation. We failed to find benefit in the primary outcome (32.1% versus 33.3%, odds ratio [OR] 0.95, 95% CI 0.32-2.84, p > 0.999) in the early versus deferred CP group. The in-hospital mortality rate was 17.9% versus 6.7% (OR 3.04, 95% CI 0.54-17.17 p = 0.246), mechanical ventilation 17.9% versus 6.7% (OR 3.04, 95% CI 0.54-17.17, p = 0.246), and prolonged hospitalization 21.4% versus 30.0% (OR 0.64, 95% CI, 0.19-2.10, p = 0.554) in the early versus deferred CP group, respectively. The viral clearance rate on day 3 (26% versus 8%, p = 0.204) and day 7 (38% versus 19%, p = 0.374) did not differ between groups. Two patients experienced serious adverse events within 6 hours after plasma transfusion. The main limitation of this study is the lack of statistical power to detect a smaller but clinically relevant therapeutic effect of CP, as well as not having confirmed neutralizing antibodies in donor before plasma infusion.
CONCLUSIONS: In the present study, we failed to find evidence of benefit in mortality, length of hospitalization, or mechanical ventilation requirement by immediate addition of CP therapy in the early stages of COVID-19 compared to its use only in case of patient deterioration.
TRIAL REGISTRATION: NCT04375098. Beltrán-Pavez, Carolina; Riquelme-Barrios, Sebastián; Oyarzún-Arrau, Aarón; Gaete-Argel, Aracelly; González-Stegmaier, Roxana; Cereceda-Solis, Karina; Aguirre, Adam; Travisany, Dante; Palma-Vejares, Ricardo; Barriga, Gonzalo P; Gaggero, Aldo; Martínez-Valdebenito, Constanza; Corre, Nicole Le; Ferrés, Marcela; Balcells, María Elvira; Fernandez, Jorge; Ramírez, Eugenio; Villarroel, Franz; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo
Insights into neutralizing antibody responses in individuals exposed to SARS-CoV-2 in Chile Journal Article
In: Sci Adv, vol. 7, no. 7, 2021, ISSN: 2375-2548.
@article{pmid33579701,
title = {Insights into neutralizing antibody responses in individuals exposed to SARS-CoV-2 in Chile},
author = {Carolina Beltrán-Pavez and Sebastián Riquelme-Barrios and Aarón Oyarzún-Arrau and Aracelly Gaete-Argel and Roxana González-Stegmaier and Karina Cereceda-Solis and Adam Aguirre and Dante Travisany and Ricardo Palma-Vejares and Gonzalo P Barriga and Aldo Gaggero and Constanza Martínez-Valdebenito and Nicole Le Corre and Marcela Ferrés and María Elvira Balcells and Jorge Fernandez and Eugenio Ramírez and Franz Villarroel and Fernando Valiente-Echeverría and Ricardo Soto-Rifo},
doi = {10.1126/sciadv.abe6855},
issn = {2375-2548},
year = {2021},
date = {2021-02-01},
journal = {Sci Adv},
volume = {7},
number = {7},
abstract = {Chile has one of the worst numbers worldwide in terms of SARS-CoV-2 positive cases and COVID-19-related deaths per million inhabitants; thus, characterization of neutralizing antibody (NAb) responses in the general population is critical to understanding of immunity at the local level. Given our inability to perform massive classical neutralization assays due to the scarce availability of BSL-3 facilities in the country, we developed and fully characterized an HIV-based SARS-CoV-2 pseudotype, which was used in a 96-well plate format to investigate NAb responses in samples from individuals exposed to SARS-CoV-2 or treated with convalescent plasma. We also identified samples with decreased or enhanced neutralization activity against the D614G spike variant compared with the wild type, indicating the relevance of this variant in host immunity. The data presented here represent the first insights into NAb responses in individuals from Chile, serving as a guide for future studies in the country.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Chile has one of the worst numbers worldwide in terms of SARS-CoV-2 positive cases and COVID-19-related deaths per million inhabitants; thus, characterization of neutralizing antibody (NAb) responses in the general population is critical to understanding of immunity at the local level. Given our inability to perform massive classical neutralization assays due to the scarce availability of BSL-3 facilities in the country, we developed and fully characterized an HIV-based SARS-CoV-2 pseudotype, which was used in a 96-well plate format to investigate NAb responses in samples from individuals exposed to SARS-CoV-2 or treated with convalescent plasma. We also identified samples with decreased or enhanced neutralization activity against the D614G spike variant compared with the wild type, indicating the relevance of this variant in host immunity. The data presented here represent the first insights into NAb responses in individuals from Chile, serving as a guide for future studies in the country. Escobar, Alejandro; Reyes-López, Felipe E; Acevedo, Mónica L; Alonso-Palomares, Luis; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo; Portillo, Hugo; Gatica, Jimena; Flores, Ivan; Nova-Lamperti, Estefanía; Barrera-Avalos, Carlos; Bono, María Rosa; Vargas, Leonardo; Simon, Valeska; Leiva-Salcedo, Elias; Vial, Cecilia; Hormazabal, Juan; Cortes, Lina Jimena; Valdés, Daniel; Sandino, Ana M; Imarai, Mónica; Acuña-Castillo, Claudio
Evaluation of the Immune Response Induced by CoronaVac 28-Day Schedule Vaccination in a Healthy Population Group Journal Article
In: Front Immunol, vol. 12, pp. 766278, 2021, ISSN: 1664-3224.
@article{pmid35173705,
title = {Evaluation of the Immune Response Induced by CoronaVac 28-Day Schedule Vaccination in a Healthy Population Group},
author = {Alejandro Escobar and Felipe E Reyes-López and Mónica L Acevedo and Luis Alonso-Palomares and Fernando Valiente-Echeverría and Ricardo Soto-Rifo and Hugo Portillo and Jimena Gatica and Ivan Flores and Estefanía Nova-Lamperti and Carlos Barrera-Avalos and María Rosa Bono and Leonardo Vargas and Valeska Simon and Elias Leiva-Salcedo and Cecilia Vial and Juan Hormazabal and Lina Jimena Cortes and Daniel Valdés and Ana M Sandino and Mónica Imarai and Claudio Acuña-Castillo},
doi = {10.3389/fimmu.2021.766278},
issn = {1664-3224},
year = {2021},
date = {2021-01-01},
journal = {Front Immunol},
volume = {12},
pages = {766278},
abstract = {CoronaVac vaccine from Sinovac Life Science is currently being used in several countries. In Chile, the effectiveness of preventing hospitalization is higher than 80% with a vaccination schedule. However, to date, there are no data about immune response induction or specific memory. For this reason, we recruited 15 volunteers without previous suspected/diagnosed COVID-19 and with negative PCR over time to evaluate the immune response to CoronaVac 28 and 90 days after the second immunization (dpi). The CoronaVac administration induces total and neutralizing anti-spike antibodies in all vaccinated volunteers at 28 and 90 dpi. Furthermore, using ELISpot analysis to assay cellular immune responses against SARS-CoV-2 spike protein, we found an increase in IFN-gamma- and Granzyme B-producing cells in vaccinated volunteers at 28 and 90 dpi. Together, our results indicate that CoronaVac induces a robust humoral immune response and cellular immune memory of at least 90 dpi.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
CoronaVac vaccine from Sinovac Life Science is currently being used in several countries. In Chile, the effectiveness of preventing hospitalization is higher than 80% with a vaccination schedule. However, to date, there are no data about immune response induction or specific memory. For this reason, we recruited 15 volunteers without previous suspected/diagnosed COVID-19 and with negative PCR over time to evaluate the immune response to CoronaVac 28 and 90 days after the second immunization (dpi). The CoronaVac administration induces total and neutralizing anti-spike antibodies in all vaccinated volunteers at 28 and 90 dpi. Furthermore, using ELISpot analysis to assay cellular immune responses against SARS-CoV-2 spike protein, we found an increase in IFN-gamma- and Granzyme B-producing cells in vaccinated volunteers at 28 and 90 dpi. Together, our results indicate that CoronaVac induces a robust humoral immune response and cellular immune memory of at least 90 dpi. Figueroa, Fabian; Vega-Gibson, Alonso; Catrileo, Joseline; Gaete-Argel, Aracelly; Riquelme-Barrios, Sebastian; Alonso-Palomares, Luis Antonio; Tapia, Lorena I; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo; Acevedo, Monica L
N -Methyladenosine Negatively Regulates Human Respiratory Syncytial Virus Replication Journal Article
In: Front Cell Dev Biol, vol. 9, pp. 739445, 2021, ISSN: 2296-634X.
@article{pmid34671602,
title = {N -Methyladenosine Negatively Regulates Human Respiratory Syncytial Virus Replication},
author = {Fabian Figueroa and Alonso Vega-Gibson and Joseline Catrileo and Aracelly Gaete-Argel and Sebastian Riquelme-Barrios and Luis Antonio Alonso-Palomares and Lorena I Tapia and Fernando Valiente-Echeverría and Ricardo Soto-Rifo and Monica L Acevedo},
doi = {10.3389/fcell.2021.739445},
issn = {2296-634X},
year = {2021},
date = {2021-01-01},
journal = {Front Cell Dev Biol},
volume = {9},
pages = {739445},
abstract = {N-methyladenosine (mA) is the most abundant internal modification described in eukaryotic mRNA and several viral RNA including human respiratory syncytial virus (HRSV). Here, we evaluated the impact of mA writers, erasers and readers on HRSV genomic RNA accumulation and inclusion bodies assembly during viral replication. We observed that the METTL3/METTL14 mA writer complex plays a negative role in HRSV protein synthesis and viral titers, while mA erasers FTO and ALKBH5 had the opposite effect. We also observed that mA readers YTHDF1-3 bind to the viral genomic RNA inducing a decrease in its intracellular levels and thus, inhibiting viral replication. Finally, we observed that overexpression of YTHDFs proteins caused a decrease in the size of inclusion bodies (IBs), accompanied by an increase in their number. METTL3 knockdown cells showed an opposite effect indicating that the dynamics of IBs assembly and coalescence are strongly affected by mA readers in a mechanism dependent on mA writers. Taken together, our results demonstrated that the mA modification negatively affects HRSV replication, possibly through a mechanism involving the assembly of inclusion bodies, the main factories of viral genomic RNA synthesis.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
N-methyladenosine (mA) is the most abundant internal modification described in eukaryotic mRNA and several viral RNA including human respiratory syncytial virus (HRSV). Here, we evaluated the impact of mA writers, erasers and readers on HRSV genomic RNA accumulation and inclusion bodies assembly during viral replication. We observed that the METTL3/METTL14 mA writer complex plays a negative role in HRSV protein synthesis and viral titers, while mA erasers FTO and ALKBH5 had the opposite effect. We also observed that mA readers YTHDF1-3 bind to the viral genomic RNA inducing a decrease in its intracellular levels and thus, inhibiting viral replication. Finally, we observed that overexpression of YTHDFs proteins caused a decrease in the size of inclusion bodies (IBs), accompanied by an increase in their number. METTL3 knockdown cells showed an opposite effect indicating that the dynamics of IBs assembly and coalescence are strongly affected by mA readers in a mechanism dependent on mA writers. Taken together, our results demonstrated that the mA modification negatively affects HRSV replication, possibly through a mechanism involving the assembly of inclusion bodies, the main factories of viral genomic RNA synthesis. Lopez-Verges, Sandra; Valiente-Echeverría, Fernando; Godoy-Faúndez, Alex; Rivas, David Fernandez; Urbani, Bernardo; Berger, Juan José; Carmona-Mora, Paulina
Call to Action: Supporting Latin American Early Career Researchers on the Quest for Sustainable Development in the Region Journal Article
In: Front Res Metr Anal, vol. 6, pp. 657120, 2021, ISSN: 2504-0537.
@article{pmid34056515,
title = {Call to Action: Supporting Latin American Early Career Researchers on the Quest for Sustainable Development in the Region},
author = {Sandra Lopez-Verges and Fernando Valiente-Echeverría and Alex Godoy-Faúndez and David Fernandez Rivas and Bernardo Urbani and Juan José Berger and Paulina Carmona-Mora},
doi = {10.3389/frma.2021.657120},
issn = {2504-0537},
year = {2021},
date = {2021-01-01},
journal = {Front Res Metr Anal},
volume = {6},
pages = {657120},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Gaete-Argel, Aracelly; Velásquez, Felipe; Márquez, Chantal L; Rojas-Araya, Barbara; Bueno-Nieto, Constanza; Marín-Rojas, Josefina; Cuevas-Zúñiga, Miguel; Soto-Rifo, Ricardo; Valiente-Echeverría, Fernando
Tellurite Promotes Stress Granules and Nuclear SG-Like Assembly in Response to Oxidative Stress and DNA Damage Journal Article
In: Front Cell Dev Biol, vol. 9, pp. 622057, 2021, ISSN: 2296-634X.
@article{pmid33681200,
title = {Tellurite Promotes Stress Granules and Nuclear SG-Like Assembly in Response to Oxidative Stress and DNA Damage},
author = {Aracelly Gaete-Argel and Felipe Velásquez and Chantal L Márquez and Barbara Rojas-Araya and Constanza Bueno-Nieto and Josefina Marín-Rojas and Miguel Cuevas-Zúñiga and Ricardo Soto-Rifo and Fernando Valiente-Echeverría},
doi = {10.3389/fcell.2021.622057},
issn = {2296-634X},
year = {2021},
date = {2021-01-01},
journal = {Front Cell Dev Biol},
volume = {9},
pages = {622057},
abstract = {Tellurium oxyanion, tellurite ( ), is a highly toxic compound for many organisms. Its presence in the environment has increased over the past years due to industrial manufacturing processes and has been associated with adverse effects on human health. Although tellurite induces the phosphorylation of eIF2α, DNA damage and oxidative stress, the molecular mechanisms related to the cellular responses to tellurite-induced stress are poorly understood. In this work, we evaluated the ability of tellurite to induce phosphorylation of eIF2α, stress granules (SGs) assembly and their relationship with DNA damage in U2OS cells. We demonstrate that tellurite promotes the assembly of cytoplasmic SGs. Unexpectedly, tellurite also induces the assembly of nuclear SGs. Interestingly, we observed that the presence of tellurite-induced nuclear SGs correlates with γH2AX foci. However, although HO also induce DNA damage, no nuclear SGs were observed. Our data show that tellurite promotes the assembly of cytoplasmic and nuclear SGs in response to oxidative stress and DNA damage, revealing a new aspect of cellular stress response mediated by the assembly of nuclear stress granules.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Tellurium oxyanion, tellurite ( ), is a highly toxic compound for many organisms. Its presence in the environment has increased over the past years due to industrial manufacturing processes and has been associated with adverse effects on human health. Although tellurite induces the phosphorylation of eIF2α, DNA damage and oxidative stress, the molecular mechanisms related to the cellular responses to tellurite-induced stress are poorly understood. In this work, we evaluated the ability of tellurite to induce phosphorylation of eIF2α, stress granules (SGs) assembly and their relationship with DNA damage in U2OS cells. We demonstrate that tellurite promotes the assembly of cytoplasmic SGs. Unexpectedly, tellurite also induces the assembly of nuclear SGs. Interestingly, we observed that the presence of tellurite-induced nuclear SGs correlates with γH2AX foci. However, although HO also induce DNA damage, no nuclear SGs were observed. Our data show that tellurite promotes the assembly of cytoplasmic and nuclear SGs in response to oxidative stress and DNA damage, revealing a new aspect of cellular stress response mediated by the assembly of nuclear stress granules. González-Stegmaier, R; Cereceda, K; Briones, J L; Beltran-Pávez, C; Oyarzún-Arrau, A; Riquelme-Barrios, S; Selman, C; Yarad, F; Mahave, M; Caglevic, C; Morales, R; Aguirre, A; Valiente-Echeverría, F; Soto-Rifo, R; Marsiglia, H; Gazitua, R; Villarroel-Espindola, F
Seroconversion and Abundance of IgG Antibodies against S1-RBD of SARS-CoV-2 and Neutralizing Activity in the Chilean Population Journal Article
In: J Immunol Res, vol. 2021, pp. 6680337, 2021, ISSN: 2314-7156.
@article{pmid33644235,
title = {Seroconversion and Abundance of IgG Antibodies against S1-RBD of SARS-CoV-2 and Neutralizing Activity in the Chilean Population},
author = {R González-Stegmaier and K Cereceda and J L Briones and C Beltran-Pávez and A Oyarzún-Arrau and S Riquelme-Barrios and C Selman and F Yarad and M Mahave and C Caglevic and R Morales and A Aguirre and F Valiente-Echeverría and R Soto-Rifo and H Marsiglia and R Gazitua and F Villarroel-Espindola},
doi = {10.1155/2021/6680337},
issn = {2314-7156},
year = {2021},
date = {2021-01-01},
journal = {J Immunol Res},
volume = {2021},
pages = {6680337},
abstract = {COVID-19 is a pandemic caused by SARS-CoV-2. In Chile, half a million people have been infected and more than 16,000 have died from COVID-19. As part of the clinical trial NCT04384588, we quantified IgG against S1-RBD of SARS-CoV-2 (anti-RBD) in recovered people in Santiago and evaluated their suitability as COVID-19 convalescent plasma donors. ELISA and a luminescent SARS-CoV-2 pseudotype were used for IgG and neutralizing antibody quantification. 72.9% of the convalescent population (468 of 639) showed seroconversion (5-55 g/mL anti-RBD IgG) and were suitable candidates for plasma donation. Analysis by gender, age, and days after symptom offset did not show significant differences. Neutralizing activity correlated with an increased concentration of anti-RBD IgG ( < 0.0001) and showed a high variability between donors. We confirmed that the majority of the Chilean patients have developed anti-SARS-CoV-2 antibodies. The quantification of anti-RBD IgG in convalescent plasma donors is necessary to increase the detection of neutralizing antibodies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
COVID-19 is a pandemic caused by SARS-CoV-2. In Chile, half a million people have been infected and more than 16,000 have died from COVID-19. As part of the clinical trial NCT04384588, we quantified IgG against S1-RBD of SARS-CoV-2 (anti-RBD) in recovered people in Santiago and evaluated their suitability as COVID-19 convalescent plasma donors. ELISA and a luminescent SARS-CoV-2 pseudotype were used for IgG and neutralizing antibody quantification. 72.9% of the convalescent population (468 of 639) showed seroconversion (5-55 g/mL anti-RBD IgG) and were suitable candidates for plasma donation. Analysis by gender, age, and days after symptom offset did not show significant differences. Neutralizing activity correlated with an increased concentration of anti-RBD IgG ( < 0.0001) and showed a high variability between donors. We confirmed that the majority of the Chilean patients have developed anti-SARS-CoV-2 antibodies. The quantification of anti-RBD IgG in convalescent plasma donors is necessary to increase the detection of neutralizing antibodies. Toro-Ascuy, Daniela; Gaete-Argel, Aracelly; Rojas-Celis, Victoria; Valiente-Echeverria, Fernando
In Situ Hybridization-Proximity Ligation Assay (ISH-PLA) to Study the Interaction of HIV-1 RNA and Remodeling Proteins Journal Article
In: Methods Mol Biol, vol. 2209, pp. 307–319, 2021, ISSN: 1940-6029.
@article{pmid33201477,
title = {In Situ Hybridization-Proximity Ligation Assay (ISH-PLA) to Study the Interaction of HIV-1 RNA and Remodeling Proteins},
author = {Daniela Toro-Ascuy and Aracelly Gaete-Argel and Victoria Rojas-Celis and Fernando Valiente-Echeverria},
doi = {10.1007/978-1-0716-0935-4_19},
issn = {1940-6029},
year = {2021},
date = {2021-01-01},
journal = {Methods Mol Biol},
volume = {2209},
pages = {307--319},
abstract = {The mechanisms involved in the posttranscriptional control of the replicative cycle of the human immunodeficiency virus (HIV), specifically the molecular events which allow the interaction between the viral genomic RNA (gRNA) and the cellular machinery for the transport, translation, or intracellular packaging, have not been yet elucidated. In this chapter, we describe the in situ hybridization-proximity ligation assay (ISH-PLA) to characterize interactions between the genomic RNA (gRNA) of HIV-1 and viral proteins or host proteins involved in nuclear export and translation initiation. We also present data that validate the ISH-PLA as a simple and useful tool to study HIV-1 gRNA-protein interactions within cells.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The mechanisms involved in the posttranscriptional control of the replicative cycle of the human immunodeficiency virus (HIV), specifically the molecular events which allow the interaction between the viral genomic RNA (gRNA) and the cellular machinery for the transport, translation, or intracellular packaging, have not been yet elucidated. In this chapter, we describe the in situ hybridization-proximity ligation assay (ISH-PLA) to characterize interactions between the genomic RNA (gRNA) of HIV-1 and viral proteins or host proteins involved in nuclear export and translation initiation. We also present data that validate the ISH-PLA as a simple and useful tool to study HIV-1 gRNA-protein interactions within cells. Beltrán-Pavez, Carolina; Alonso-Palomares, Luis A; Valiente-Echeverría, Fernando; Gaggero, Aldo; Soto-Rifo, Ricardo; Barriga, Gonzalo P
Accuracy of a RT-qPCR SARS-CoV-2 detection assay without prior RNA extraction Journal Article
In: J Virol Methods, vol. 287, pp. 113969, 2021, ISSN: 1879-0984.
@article{pmid32918932,
title = {Accuracy of a RT-qPCR SARS-CoV-2 detection assay without prior RNA extraction},
author = {Carolina Beltrán-Pavez and Luis A Alonso-Palomares and Fernando Valiente-Echeverría and Aldo Gaggero and Ricardo Soto-Rifo and Gonzalo P Barriga},
doi = {10.1016/j.jviromet.2020.113969},
issn = {1879-0984},
year = {2021},
date = {2021-01-01},
journal = {J Virol Methods},
volume = {287},
pages = {113969},
abstract = {The current COVID-19 pandemic constitutes a threat to the population worldwide with over 21 million infected people. There is an urgent need for the development of rapid and massive detection tools as well as the identification and isolation of infected individuals. we sought to evaluate different RT-qPCR kits and protocols to evaluate the best approach to be used omitting an RNA extraction step. We have investigated the sensitivity and performance of different commercially available RT-qPCR kits in detecting SARS-CoV-2 using 80 extracted RNA and NSS from COVID-19 diagnosed patients. We evaluated the ability of each kit to detect viral RNA from both kit-extracted or directly from a pre-boiled NSS observing that direct RNA detection is possible when Ct values are lower than 30 with the three kits tested. Since SARS-CoV-2 testing in most locations occurs once COVID-19 symptoms are evident and, therefore, viral loads are expected to be high, our protocol will be useful in supporting SARS-CoV-2 diagnosis, especially in America where COVID-19 cases have exploded in the recent weeks as well as in low- and middle-income countries, which would not have massive access to kit-based diagnosis. The information provided in this work paves the way for the development of more efficient SARS-CoV-2 detection approaches avoiding an RNA extraction step.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The current COVID-19 pandemic constitutes a threat to the population worldwide with over 21 million infected people. There is an urgent need for the development of rapid and massive detection tools as well as the identification and isolation of infected individuals. we sought to evaluate different RT-qPCR kits and protocols to evaluate the best approach to be used omitting an RNA extraction step. We have investigated the sensitivity and performance of different commercially available RT-qPCR kits in detecting SARS-CoV-2 using 80 extracted RNA and NSS from COVID-19 diagnosed patients. We evaluated the ability of each kit to detect viral RNA from both kit-extracted or directly from a pre-boiled NSS observing that direct RNA detection is possible when Ct values are lower than 30 with the three kits tested. Since SARS-CoV-2 testing in most locations occurs once COVID-19 symptoms are evident and, therefore, viral loads are expected to be high, our protocol will be useful in supporting SARS-CoV-2 diagnosis, especially in America where COVID-19 cases have exploded in the recent weeks as well as in low- and middle-income countries, which would not have massive access to kit-based diagnosis. The information provided in this work paves the way for the development of more efficient SARS-CoV-2 detection approaches avoiding an RNA extraction step.2020
Velásquez, Felipe; Marín-Rojas, Josefina; Soto-Rifo, Ricardo; Torres, Alexia; Canto, Felipe Del; Valiente-Echeverría, Fernando
HS and Enterotoxigenic Hinder Stress Granule Assembly Journal Article
In: Microorganisms, vol. 9, no. 1, 2020, ISSN: 2076-2607.
@article{pmid33374562,
title = { HS and Enterotoxigenic Hinder Stress Granule Assembly},
author = {Felipe Velásquez and Josefina Marín-Rojas and Ricardo Soto-Rifo and Alexia Torres and Felipe Del Canto and Fernando Valiente-Echeverría},
doi = {10.3390/microorganisms9010017},
issn = {2076-2607},
year = {2020},
date = {2020-12-01},
journal = {Microorganisms},
volume = {9},
number = {1},
abstract = {, one of the most abundant bacterial species in the human gut microbiota, has developed a mutualistic relationship with its host, regulating immunological responses. In contrast, enterotoxigenic (ETEC), one of the main etiologic agents of diarrheal morbidity and mortality in children under the age of five in developing countries, has developed mechanisms to reduce the immune-activator effect to carry out a successful infection. Following infection, the host cell initiates the shutting-off of protein synthesis and stress granule (SG) assembly. This is mostly mediated by the phosphorylation of translation initiator factor 2α (eIF2α). We therefore evaluated the ability of a non-pathogenic strain ( HS) and an ETEC strain (ETEC 1766a) to induce stress granule assembly, even in response to exogenous stresses. In this work, we found that infection with HS or ETEC 1766a prevents SG assembly in Caco-2 cells treated with sodium arsenite (Ars) after infection. We also show that this effect occurs through an eIF2α phosphorylation (eIF2α-P)-dependent mechanism. Understanding how bacteria counters host stress responses will lay the groundwork for new therapeutic strategies to bolster host cell immune defenses against these pathogens.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
, one of the most abundant bacterial species in the human gut microbiota, has developed a mutualistic relationship with its host, regulating immunological responses. In contrast, enterotoxigenic (ETEC), one of the main etiologic agents of diarrheal morbidity and mortality in children under the age of five in developing countries, has developed mechanisms to reduce the immune-activator effect to carry out a successful infection. Following infection, the host cell initiates the shutting-off of protein synthesis and stress granule (SG) assembly. This is mostly mediated by the phosphorylation of translation initiator factor 2α (eIF2α). We therefore evaluated the ability of a non-pathogenic strain ( HS) and an ETEC strain (ETEC 1766a) to induce stress granule assembly, even in response to exogenous stresses. In this work, we found that infection with HS or ETEC 1766a prevents SG assembly in Caco-2 cells treated with sodium arsenite (Ars) after infection. We also show that this effect occurs through an eIF2α phosphorylation (eIF2α-P)-dependent mechanism. Understanding how bacteria counters host stress responses will lay the groundwork for new therapeutic strategies to bolster host cell immune defenses against these pathogens. Oyarzún-Arrau, Aarón; Alonso-Palomares, Luis; Valiente-Echeverría, Fernando; Osorio, Fabiola; Soto-Rifo, Ricardo
Crosstalk between RNA Metabolism and Cellular Stress Responses during Zika Virus Replication Journal Article
In: Pathogens, vol. 9, no. 3, 2020, ISSN: 2076-0817.
@article{pmid32106582,
title = {Crosstalk between RNA Metabolism and Cellular Stress Responses during Zika Virus Replication},
author = {Aarón Oyarzún-Arrau and Luis Alonso-Palomares and Fernando Valiente-Echeverría and Fabiola Osorio and Ricardo Soto-Rifo},
doi = {10.3390/pathogens9030158},
issn = {2076-0817},
year = {2020},
date = {2020-02-01},
journal = {Pathogens},
volume = {9},
number = {3},
abstract = {Zika virus (ZIKV) is a mosquito-borne virus associated with neurological disorders such as Guillain-Barré syndrome and microcephaly. In humans, ZIKV is able to replicate in cell types from different tissues including placental cells, neurons, and microglia. This intricate virus-cell interaction is accompanied by virally induced changes in the infected cell aimed to promote viral replication as well as cellular responses aimed to counteract or tolerate the virus. Early in the infection, the 11-kb positive-sense RNA genome recruit ribosomes in the cytoplasm and the complex is translocated to the endoplasmic reticulum (ER) for viral protein synthesis. In this process, ZIKV replication is known to induce cellular stress, which triggers both the expression of innate immune genes and the phosphorylation of eukaryotic translation initiation factor 2 (eIF2α), shutting-off host protein synthesis. Remodeling of the ER during ZIKV replication also triggers the unfolded protein response (UPR), which induces changes in the cellular transcriptional landscapes aimed to tolerate infection or trigger apoptosis. Alternatively, ZIKV replication induces changes in the adenosine methylation patterns of specific host mRNAs, which have different consequences in viral replication and cellular fate. In addition, the ZIKV RNA genome undergoes adenosine methylation by the host machinery, which results in the inhibition of viral replication. However, despite these relevant findings, the full scope of these processes to the outcome of infection remains poorly elucidated. This review summarizes relevant aspects of the complex crosstalk between RNA metabolism and cellular stress responses against ZIKV and discusses their possible impact on viral pathogenesis.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Zika virus (ZIKV) is a mosquito-borne virus associated with neurological disorders such as Guillain-Barré syndrome and microcephaly. In humans, ZIKV is able to replicate in cell types from different tissues including placental cells, neurons, and microglia. This intricate virus-cell interaction is accompanied by virally induced changes in the infected cell aimed to promote viral replication as well as cellular responses aimed to counteract or tolerate the virus. Early in the infection, the 11-kb positive-sense RNA genome recruit ribosomes in the cytoplasm and the complex is translocated to the endoplasmic reticulum (ER) for viral protein synthesis. In this process, ZIKV replication is known to induce cellular stress, which triggers both the expression of innate immune genes and the phosphorylation of eukaryotic translation initiation factor 2 (eIF2α), shutting-off host protein synthesis. Remodeling of the ER during ZIKV replication also triggers the unfolded protein response (UPR), which induces changes in the cellular transcriptional landscapes aimed to tolerate infection or trigger apoptosis. Alternatively, ZIKV replication induces changes in the adenosine methylation patterns of specific host mRNAs, which have different consequences in viral replication and cellular fate. In addition, the ZIKV RNA genome undergoes adenosine methylation by the host machinery, which results in the inhibition of viral replication. However, despite these relevant findings, the full scope of these processes to the outcome of infection remains poorly elucidated. This review summarizes relevant aspects of the complex crosstalk between RNA metabolism and cellular stress responses against ZIKV and discusses their possible impact on viral pathogenesis.2019
Rojas-Celis, Victoria; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo; Toro-Ascuy, Daniela
New Challenges of HIV-1 Infection: How HIV-1 Attacks and Resides in the Central Nervous System Journal Article
In: Cells, vol. 8, no. 10, 2019, ISSN: 2073-4409.
@article{pmid31614895,
title = {New Challenges of HIV-1 Infection: How HIV-1 Attacks and Resides in the Central Nervous System},
author = {Victoria Rojas-Celis and Fernando Valiente-Echeverría and Ricardo Soto-Rifo and Daniela Toro-Ascuy},
doi = {10.3390/cells8101245},
issn = {2073-4409},
year = {2019},
date = {2019-10-01},
journal = {Cells},
volume = {8},
number = {10},
abstract = {Acquired immunodeficiency syndrome (AIDS) has become one of the most devastating pandemics in recorded history. The main causal agent of AIDS is the human immunodeficiency virus (HIV), which infects various cell types of the immune system that express the CD4 receptor on their surfaces. Today, combined antiretroviral therapy (cART) is the standard treatment for all people with HIV; although it has improved the quality of life of people living with HIV (PLWH), it cannot eliminate the latent reservoir of the virus. Therefore HIV/AIDS has turned from a fatal disease to a chronic disease requiring lifelong treatment. Despite significant viral load suppression, it has been observed that at least half of patients under cART present HIV-associated neurocognitive disorders (HAND), which have been related to HIV-1 infection and replication in the central nervous system (CNS). Several studies have focused on elucidating the mechanism by which HIV-1 can invade the CNS and how it can generate the effects seen in HAND. This review summarizes the research on HIV-1 and its interaction with the CNS with an emphasis on the generation of HAND, how the virus enters the CNS, the relationship between HIV-1 and cells of the CNS, and the effect of cART on these cells.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Acquired immunodeficiency syndrome (AIDS) has become one of the most devastating pandemics in recorded history. The main causal agent of AIDS is the human immunodeficiency virus (HIV), which infects various cell types of the immune system that express the CD4 receptor on their surfaces. Today, combined antiretroviral therapy (cART) is the standard treatment for all people with HIV; although it has improved the quality of life of people living with HIV (PLWH), it cannot eliminate the latent reservoir of the virus. Therefore HIV/AIDS has turned from a fatal disease to a chronic disease requiring lifelong treatment. Despite significant viral load suppression, it has been observed that at least half of patients under cART present HIV-associated neurocognitive disorders (HAND), which have been related to HIV-1 infection and replication in the central nervous system (CNS). Several studies have focused on elucidating the mechanism by which HIV-1 can invade the CNS and how it can generate the effects seen in HAND. This review summarizes the research on HIV-1 and its interaction with the CNS with an emphasis on the generation of HAND, how the virus enters the CNS, the relationship between HIV-1 and cells of the CNS, and the effect of cART on these cells. Gaete-Argel, Aracelly; Márquez, Chantal L; Barriga, Gonzalo P; Soto-Rifo, Ricardo; Valiente-Echeverría, Fernando
Strategies for Success. Viral Infections and Membraneless Organelles Journal Article
In: Front Cell Infect Microbiol, vol. 9, pp. 336, 2019, ISSN: 2235-2988.
@article{pmid31681621,
title = {Strategies for Success. Viral Infections and Membraneless Organelles},
author = {Aracelly Gaete-Argel and Chantal L Márquez and Gonzalo P Barriga and Ricardo Soto-Rifo and Fernando Valiente-Echeverría},
doi = {10.3389/fcimb.2019.00336},
issn = {2235-2988},
year = {2019},
date = {2019-01-01},
journal = {Front Cell Infect Microbiol},
volume = {9},
pages = {336},
abstract = {Regulation of RNA homeostasis or "RNAstasis" is a central step in eukaryotic gene expression. From transcription to decay, cellular messenger RNAs (mRNAs) associate with specific proteins in order to regulate their entire cycle, including mRNA localization, translation and degradation, among others. The best characterized of such RNA-protein complexes, today named membraneless organelles, are Stress Granules (SGs) and Processing Bodies (PBs) which are involved in RNA storage and RNA decay/storage, respectively. Given that SGs and PBs are generally associated with repression of gene expression, viruses have evolved different mechanisms to counteract their assembly or to use them in their favor to successfully replicate within the host environment. In this review we summarize the current knowledge about the viral regulation of SGs and PBs, which could be a potential novel target for the development of broad-spectrum antiviral therapies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Regulation of RNA homeostasis or "RNAstasis" is a central step in eukaryotic gene expression. From transcription to decay, cellular messenger RNAs (mRNAs) associate with specific proteins in order to regulate their entire cycle, including mRNA localization, translation and degradation, among others. The best characterized of such RNA-protein complexes, today named membraneless organelles, are Stress Granules (SGs) and Processing Bodies (PBs) which are involved in RNA storage and RNA decay/storage, respectively. Given that SGs and PBs are generally associated with repression of gene expression, viruses have evolved different mechanisms to counteract their assembly or to use them in their favor to successfully replicate within the host environment. In this review we summarize the current knowledge about the viral regulation of SGs and PBs, which could be a potential novel target for the development of broad-spectrum antiviral therapies.2018
Toro-Ascuy, Daniela; Rojas-Araya, Bárbara; García-de-Gracia, Francisco; Rojas-Fuentes, Cecilia; Pereira-Montecinos, Camila; Gaete-Argel, Aracelly; Valiente-Echeverría, Fernando; Ohlmann, Théophile; Soto-Rifo, Ricardo
A Rev-CBP80-eIF4AI complex drives Gag synthesis from the HIV-1 unspliced mRNA Journal Article
In: Nucleic Acids Res, vol. 46, no. 21, pp. 11539–11552, 2018, ISSN: 1362-4962.
@article{pmid30239828,
title = {A Rev-CBP80-eIF4AI complex drives Gag synthesis from the HIV-1 unspliced mRNA},
author = {Daniela Toro-Ascuy and Bárbara Rojas-Araya and Francisco García-de-Gracia and Cecilia Rojas-Fuentes and Camila Pereira-Montecinos and Aracelly Gaete-Argel and Fernando Valiente-Echeverría and Théophile Ohlmann and Ricardo Soto-Rifo},
doi = {10.1093/nar/gky851},
issn = {1362-4962},
year = {2018},
date = {2018-11-01},
journal = {Nucleic Acids Res},
volume = {46},
number = {21},
pages = {11539--11552},
abstract = {Gag synthesis from the full-length unspliced mRNA is critical for the production of the viral progeny during human immunodeficiency virus type-1 (HIV-1) replication. While most spliced mRNAs follow the canonical gene expression pathway in which the recruitment of the nuclear cap-binding complex (CBC) and the exon junction complex (EJC) largely stimulates the rates of nuclear export and translation, the unspliced mRNA relies on the viral protein Rev to reach the cytoplasm and recruit the host translational machinery. Here, we confirm that Rev ensures high levels of Gag synthesis by driving nuclear export and translation of the unspliced mRNA. These functions of Rev are supported by the CBC subunit CBP80, which binds Rev and the unspliced mRNA in the nucleus and the cytoplasm. We also demonstrate that Rev interacts with the DEAD-box RNA helicase eIF4AI, which translocates to the nucleus and cooperates with the viral protein to promote Gag synthesis. Finally, we show that the Rev/RRE axis is important for the assembly of a CBP80-eIF4AI complex onto the unspliced mRNA. Together, our results provide further evidence towards the understanding of the molecular mechanisms by which Rev drives Gag synthesis from the unspliced mRNA during HIV-1 replication.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Gag synthesis from the full-length unspliced mRNA is critical for the production of the viral progeny during human immunodeficiency virus type-1 (HIV-1) replication. While most spliced mRNAs follow the canonical gene expression pathway in which the recruitment of the nuclear cap-binding complex (CBC) and the exon junction complex (EJC) largely stimulates the rates of nuclear export and translation, the unspliced mRNA relies on the viral protein Rev to reach the cytoplasm and recruit the host translational machinery. Here, we confirm that Rev ensures high levels of Gag synthesis by driving nuclear export and translation of the unspliced mRNA. These functions of Rev are supported by the CBC subunit CBP80, which binds Rev and the unspliced mRNA in the nucleus and the cytoplasm. We also demonstrate that Rev interacts with the DEAD-box RNA helicase eIF4AI, which translocates to the nucleus and cooperates with the viral protein to promote Gag synthesis. Finally, we show that the Rev/RRE axis is important for the assembly of a CBP80-eIF4AI complex onto the unspliced mRNA. Together, our results provide further evidence towards the understanding of the molecular mechanisms by which Rev drives Gag synthesis from the unspliced mRNA during HIV-1 replication. Riquelme-Barrios, Sebastián; Pereira-Montecinos, Camila; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo
Emerging Roles of N-Methyladenosine on HIV-1 RNA Metabolism and Viral Replication Journal Article
In: Front Microbiol, vol. 9, pp. 576, 2018, ISSN: 1664-302X.
@article{pmid29643844,
title = {Emerging Roles of N-Methyladenosine on HIV-1 RNA Metabolism and Viral Replication},
author = {Sebastián Riquelme-Barrios and Camila Pereira-Montecinos and Fernando Valiente-Echeverría and Ricardo Soto-Rifo},
doi = {10.3389/fmicb.2018.00576},
issn = {1664-302X},
year = {2018},
date = {2018-01-01},
journal = {Front Microbiol},
volume = {9},
pages = {576},
abstract = {N-methyladenosine (mA) is the most abundant internal modification present in Eukaryotic mRNA. The functions of this chemical modification are mediated by mA-binding proteins (mA readers) and regulated by methyltransferases (mA writers) and demethylases (mA erasers), which together are proposed to be responsible of a new layer of post-transcriptional control of gene expression. Despite the presence of mA in a retroviral genome was reported more than 40 years ago, the recent development of sequencing-based technologies allowing the mapping of mA in a transcriptome-wide manner made it possible to identify the topology and dynamics of mA during replication of HIV-1 as well as other viruses. As such, three independent groups recently reported the presence of mA along the HIV-1 genomic RNA (gRNA) and described the impact of cellular mA writers, erasers and readers on different steps of viral RNA metabolism and replication. Interestingly, while two groups reported a positive role of mA at different steps of viral gene expression it was also proposed that the presence of mA within the gRNA reduces viral infectivity by inducing the early degradation of the incoming viral genome. This review summarizes the recent advances in this emerging field and discusses the relevance of mA during HIV-1 replication.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
N-methyladenosine (mA) is the most abundant internal modification present in Eukaryotic mRNA. The functions of this chemical modification are mediated by mA-binding proteins (mA readers) and regulated by methyltransferases (mA writers) and demethylases (mA erasers), which together are proposed to be responsible of a new layer of post-transcriptional control of gene expression. Despite the presence of mA in a retroviral genome was reported more than 40 years ago, the recent development of sequencing-based technologies allowing the mapping of mA in a transcriptome-wide manner made it possible to identify the topology and dynamics of mA during replication of HIV-1 as well as other viruses. As such, three independent groups recently reported the presence of mA along the HIV-1 genomic RNA (gRNA) and described the impact of cellular mA writers, erasers and readers on different steps of viral RNA metabolism and replication. Interestingly, while two groups reported a positive role of mA at different steps of viral gene expression it was also proposed that the presence of mA within the gRNA reduces viral infectivity by inducing the early degradation of the incoming viral genome. This review summarizes the recent advances in this emerging field and discusses the relevance of mA during HIV-1 replication.2017
Cinti, Alessandro; Sage, Valerie Le; Milev, Miroslav P; Valiente-Echeverría, Fernando; Crossie, Christina; Miron, Marie-Joelle; Panté, Nelly; Olivier, Martin; Mouland, Andrew J
HIV-1 enhances mTORC1 activity and repositions lysosomes to the periphery by co-opting Rag GTPases Journal Article
In: Sci Rep, vol. 7, no. 1, pp. 5515, 2017, ISSN: 2045-2322.
@article{pmid28710431,
title = {HIV-1 enhances mTORC1 activity and repositions lysosomes to the periphery by co-opting Rag GTPases},
author = {Alessandro Cinti and Valerie Le Sage and Miroslav P Milev and Fernando Valiente-Echeverría and Christina Crossie and Marie-Joelle Miron and Nelly Panté and Martin Olivier and Andrew J Mouland},
doi = {10.1038/s41598-017-05410-0},
issn = {2045-2322},
year = {2017},
date = {2017-07-01},
journal = {Sci Rep},
volume = {7},
number = {1},
pages = {5515},
abstract = {HIV-1 co-opts several host machinery to generate a permissive environment for viral replication and transmission. In this work we reveal how HIV-1 impacts the host translation and intracellular vesicular trafficking machineries for protein synthesis and to impede the physiological late endosome/lysosome (LEL) trafficking in stressful conditions. First, HIV-1 enhances the activity of the master regulator of protein synthesis, the mammalian target of rapamycin (mTOR). Second, the virus commandeers mTOR-associated late endosome/lysosome (LEL) trafficking and counteracts metabolic and environmental stress-induced intracellular repositioning of LEL. We then show that the small Rag GTPases, RagA and RagB, are required for the HIV-1-mediated LEL repositioning that is likely mediated by interactions between the Rags and the viral proteins, Gag and Vif. siRNA-mediated depletion of RagA and RagB leads to a loss in mTOR association to LEL and to a blockade of viral particle assembly and release at the plasma membrane with a marked concomitant reduction in virus production. These results show that HIV-1 co-opts fundamental mechanisms that regulate LEL motility and positioning and support the notion that LEL positioning is critical for HIV-1 replication.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
HIV-1 co-opts several host machinery to generate a permissive environment for viral replication and transmission. In this work we reveal how HIV-1 impacts the host translation and intracellular vesicular trafficking machineries for protein synthesis and to impede the physiological late endosome/lysosome (LEL) trafficking in stressful conditions. First, HIV-1 enhances the activity of the master regulator of protein synthesis, the mammalian target of rapamycin (mTOR). Second, the virus commandeers mTOR-associated late endosome/lysosome (LEL) trafficking and counteracts metabolic and environmental stress-induced intracellular repositioning of LEL. We then show that the small Rag GTPases, RagA and RagB, are required for the HIV-1-mediated LEL repositioning that is likely mediated by interactions between the Rags and the viral proteins, Gag and Vif. siRNA-mediated depletion of RagA and RagB leads to a loss in mTOR association to LEL and to a blockade of viral particle assembly and release at the plasma membrane with a marked concomitant reduction in virus production. These results show that HIV-1 co-opts fundamental mechanisms that regulate LEL motility and positioning and support the notion that LEL positioning is critical for HIV-1 replication. Rojas-Mancilla, Edgardo; Oyarce, Alexis; Verdugo, Viviana; Morales-Verdejo, Cesar; Echeverria, Cesar; Velásquez, Felipe; Chnaiderman, Jonas; Valiente-Echeverría, Fernando; Ramirez-Tagle, Rodrigo
The [Mo₆Cl] Cluster is Biologically Secure and Has Anti-Rotavirus Activity In Vitro Journal Article
In: Molecules, vol. 22, no. 7, 2017, ISSN: 1420-3049.
@article{pmid28678175,
title = {The [Mo₆Cl] Cluster is Biologically Secure and Has Anti-Rotavirus Activity In Vitro},
author = {Edgardo Rojas-Mancilla and Alexis Oyarce and Viviana Verdugo and Cesar Morales-Verdejo and Cesar Echeverria and Felipe Velásquez and Jonas Chnaiderman and Fernando Valiente-Echeverría and Rodrigo Ramirez-Tagle},
doi = {10.3390/molecules22071108},
issn = {1420-3049},
year = {2017},
date = {2017-07-01},
journal = {Molecules},
volume = {22},
number = {7},
abstract = {The molybdenum cluster [Mo₆Cl] is a fluorescent component with potential for use in cell labelling and pharmacology. Biological safety and antiviral properties of the cluster are as yet unknown. Here, we show the effect of acute exposition of human cells and red blood cells to the molybdenum cluster and its interaction with proteins and antiviral activity in vitro. We measured cell viability of HepG2 and EA.hy926 cell lines exposed to increasing concentrations of the cluster (0.1 to 250 µM), by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. Hemolysis and morphological alterations of red blood cells, obtained from healthy donors, exposed to the cluster (10 to 200 µM) at 37 °C were analyzed. Furthermore, quenching of tryptophan residues of albumin was performed. Finally, plaque formation by rotavirus SA11 in MA104 cells treated with the cluster (100 to 300 µM) were analyzed. We found that all doses of the cluster showed similar cell viability, hemolysis, and morphology values, compared to control. Quenching of tryptophan residues of albumin suggests a protein-cluster complex formation. Finally, the cluster showed antiviral activity at 300 µM. These results indicate that the cluster [Mo₆Cl] could be intravenously administered in animals at therapeutic doses for further in vivo studies and might be studied as an antiviral agent.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The molybdenum cluster [Mo₆Cl] is a fluorescent component with potential for use in cell labelling and pharmacology. Biological safety and antiviral properties of the cluster are as yet unknown. Here, we show the effect of acute exposition of human cells and red blood cells to the molybdenum cluster and its interaction with proteins and antiviral activity in vitro. We measured cell viability of HepG2 and EA.hy926 cell lines exposed to increasing concentrations of the cluster (0.1 to 250 µM), by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. Hemolysis and morphological alterations of red blood cells, obtained from healthy donors, exposed to the cluster (10 to 200 µM) at 37 °C were analyzed. Furthermore, quenching of tryptophan residues of albumin was performed. Finally, plaque formation by rotavirus SA11 in MA104 cells treated with the cluster (100 to 300 µM) were analyzed. We found that all doses of the cluster showed similar cell viability, hemolysis, and morphology values, compared to control. Quenching of tryptophan residues of albumin suggests a protein-cluster complex formation. Finally, the cluster showed antiviral activity at 300 µM. These results indicate that the cluster [Mo₆Cl] could be intravenously administered in animals at therapeutic doses for further in vivo studies and might be studied as an antiviral agent. Pereira-Montecinos, Camila; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo
Epitranscriptomic regulation of viral replication Journal Article
In: Biochim Biophys Acta Gene Regul Mech, vol. 1860, no. 4, pp. 460–471, 2017, ISSN: 1874-9399.
@article{pmid28219769,
title = {Epitranscriptomic regulation of viral replication},
author = {Camila Pereira-Montecinos and Fernando Valiente-Echeverría and Ricardo Soto-Rifo},
doi = {10.1016/j.bbagrm.2017.02.002},
issn = {1874-9399},
year = {2017},
date = {2017-04-01},
journal = {Biochim Biophys Acta Gene Regul Mech},
volume = {1860},
number = {4},
pages = {460--471},
abstract = {RNA plays central roles in biology and novel functions and regulation mechanisms are constantly emerging. To accomplish some of their functions within the cell, RNA molecules undergo hundreds of chemical modifications from which N6-methyladenosine (mA), inosine (I), pseudouridine (ψ) and 5-methylcytosine (5mC) have been described in eukaryotic mRNA. Interestingly, the mA modification was shown to be reversible, adding novel layers of regulation of gene expression through what is now recognized as epitranscriptomics. The development of molecular mapping strategies coupled to next generation sequencing allowed the identification of thousand of modified transcripts in different tissues and under different physiological conditions such as viral infections. As intracellular parasites, viruses are confronted to cellular RNA modifying enzymes and, as a consequence, viral RNA can be chemically modified at some stages of the replication cycle. This review focuses on the chemical modifications of viral RNA and the impact that these modifications have on viral gene expression and the output of infection. A special emphasis is given to mA, which was recently shown to play important yet controversial roles in different steps of the HIV-1, HCV and ZIKV replication cycles.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
RNA plays central roles in biology and novel functions and regulation mechanisms are constantly emerging. To accomplish some of their functions within the cell, RNA molecules undergo hundreds of chemical modifications from which N6-methyladenosine (mA), inosine (I), pseudouridine (ψ) and 5-methylcytosine (5mC) have been described in eukaryotic mRNA. Interestingly, the mA modification was shown to be reversible, adding novel layers of regulation of gene expression through what is now recognized as epitranscriptomics. The development of molecular mapping strategies coupled to next generation sequencing allowed the identification of thousand of modified transcripts in different tissues and under different physiological conditions such as viral infections. As intracellular parasites, viruses are confronted to cellular RNA modifying enzymes and, as a consequence, viral RNA can be chemically modified at some stages of the replication cycle. This review focuses on the chemical modifications of viral RNA and the impact that these modifications have on viral gene expression and the output of infection. A special emphasis is given to mA, which was recently shown to play important yet controversial roles in different steps of the HIV-1, HCV and ZIKV replication cycles.2016
Toro-Ascuy, Daniela; Rojas-Araya, Bárbara; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo
Interactions between the HIV-1 Unspliced mRNA and Host mRNA Decay Machineries Journal Article
In: Viruses, vol. 8, no. 11, 2016, ISSN: 1999-4915.
@article{pmid27886048,
title = {Interactions between the HIV-1 Unspliced mRNA and Host mRNA Decay Machineries},
author = {Daniela Toro-Ascuy and Bárbara Rojas-Araya and Fernando Valiente-Echeverría and Ricardo Soto-Rifo},
doi = {10.3390/v8110320},
issn = {1999-4915},
year = {2016},
date = {2016-11-01},
journal = {Viruses},
volume = {8},
number = {11},
abstract = {The human immunodeficiency virus type-1 (HIV-1) unspliced transcript is used both as mRNA for the synthesis of structural proteins and as the packaged genome. Given the presence of retained introns and instability AU-rich sequences, this viral transcript is normally retained and degraded in the nucleus of host cells unless the viral protein REV is present. As such, the stability of the HIV-1 unspliced mRNA must be particularly controlled in the nucleus and the cytoplasm in order to ensure proper levels of this viral mRNA for translation and viral particle formation. During its journey, the HIV-1 unspliced mRNA assembles into highly specific messenger ribonucleoproteins (mRNPs) containing many different host proteins, amongst which are well-known regulators of cytoplasmic mRNA decay pathways such as up-frameshift suppressor 1 homolog (UPF1), Staufen double-stranded RNA binding protein 1/2 (STAU1/2), or components of miRNA-induced silencing complex (miRISC) and processing bodies (PBs). More recently, the HIV-1 unspliced mRNA was shown to contain ⁶-methyladenosine (m⁶A), allowing the recruitment of YTH ⁶-methyladenosine RNA binding protein 2 (YTHDF2), an m⁶A reader host protein involved in mRNA decay. Interestingly, these host proteins involved in mRNA decay were shown to play positive roles in viral gene expression and viral particle assembly, suggesting that HIV-1 interacts with mRNA decay components to successfully accomplish viral replication. This review summarizes the state of the art in terms of the interactions between HIV-1 unspliced mRNA and components of different host mRNA decay machineries.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The human immunodeficiency virus type-1 (HIV-1) unspliced transcript is used both as mRNA for the synthesis of structural proteins and as the packaged genome. Given the presence of retained introns and instability AU-rich sequences, this viral transcript is normally retained and degraded in the nucleus of host cells unless the viral protein REV is present. As such, the stability of the HIV-1 unspliced mRNA must be particularly controlled in the nucleus and the cytoplasm in order to ensure proper levels of this viral mRNA for translation and viral particle formation. During its journey, the HIV-1 unspliced mRNA assembles into highly specific messenger ribonucleoproteins (mRNPs) containing many different host proteins, amongst which are well-known regulators of cytoplasmic mRNA decay pathways such as up-frameshift suppressor 1 homolog (UPF1), Staufen double-stranded RNA binding protein 1/2 (STAU1/2), or components of miRNA-induced silencing complex (miRISC) and processing bodies (PBs). More recently, the HIV-1 unspliced mRNA was shown to contain ⁶-methyladenosine (m⁶A), allowing the recruitment of YTH ⁶-methyladenosine RNA binding protein 2 (YTHDF2), an m⁶A reader host protein involved in mRNA decay. Interestingly, these host proteins involved in mRNA decay were shown to play positive roles in viral gene expression and viral particle assembly, suggesting that HIV-1 interacts with mRNA decay components to successfully accomplish viral replication. This review summarizes the state of the art in terms of the interactions between HIV-1 unspliced mRNA and components of different host mRNA decay machineries. Poblete-Durán, Natalia; Prades-Pérez, Yara; Vera-Otarola, Jorge; Soto-Rifo, Ricardo; Valiente-Echeverría, Fernando
Who Regulates Whom? An Overview of RNA Granules and Viral Infections Journal Article
In: Viruses, vol. 8, no. 7, 2016, ISSN: 1999-4915.
@article{pmid27367717,
title = {Who Regulates Whom? An Overview of RNA Granules and Viral Infections},
author = {Natalia Poblete-Durán and Yara Prades-Pérez and Jorge Vera-Otarola and Ricardo Soto-Rifo and Fernando Valiente-Echeverría},
doi = {10.3390/v8070180},
issn = {1999-4915},
year = {2016},
date = {2016-06-01},
journal = {Viruses},
volume = {8},
number = {7},
abstract = {After viral infection, host cells respond by mounting an anti-viral stress response in order to create a hostile atmosphere for viral replication, leading to the shut-off of mRNA translation (protein synthesis) and the assembly of RNA granules. Two of these RNA granules have been well characterized in yeast and mammalian cells, stress granules (SGs), which are translationally silent sites of RNA triage and processing bodies (PBs), which are involved in mRNA degradation. This review discusses the role of these RNA granules in the evasion of anti-viral stress responses through virus-induced remodeling of cellular ribonucleoproteins (RNPs).},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
After viral infection, host cells respond by mounting an anti-viral stress response in order to create a hostile atmosphere for viral replication, leading to the shut-off of mRNA translation (protein synthesis) and the assembly of RNA granules. Two of these RNA granules have been well characterized in yeast and mammalian cells, stress granules (SGs), which are translationally silent sites of RNA triage and processing bodies (PBs), which are involved in mRNA degradation. This review discusses the role of these RNA granules in the evasion of anti-viral stress responses through virus-induced remodeling of cellular ribonucleoproteins (RNPs). Fröhlich, Alvaro; Rojas-Araya, Bárbara; Pereira-Montecinos, Camila; Dellarossa, Alessandra; Toro-Ascuy, Daniela; Prades-Pérez, Yara; García-de-Gracia, Francisco; Garcés-Alday, Andrea; Rubilar, Paulina S; Valiente-Echeverría, Fernando; Ohlmann, Théophile; Soto-Rifo, Ricardo
DEAD-box RNA helicase DDX3 connects CRM1-dependent nuclear export and translation of the HIV-1 unspliced mRNA through its N-terminal domain Journal Article
In: Biochim Biophys Acta, vol. 1859, no. 5, pp. 719–730, 2016, ISSN: 0006-3002.
@article{pmid27012366,
title = {DEAD-box RNA helicase DDX3 connects CRM1-dependent nuclear export and translation of the HIV-1 unspliced mRNA through its N-terminal domain},
author = {Alvaro Fröhlich and Bárbara Rojas-Araya and Camila Pereira-Montecinos and Alessandra Dellarossa and Daniela Toro-Ascuy and Yara Prades-Pérez and Francisco García-de-Gracia and Andrea Garcés-Alday and Paulina S Rubilar and Fernando Valiente-Echeverría and Théophile Ohlmann and Ricardo Soto-Rifo},
doi = {10.1016/j.bbagrm.2016.03.009},
issn = {0006-3002},
year = {2016},
date = {2016-05-01},
journal = {Biochim Biophys Acta},
volume = {1859},
number = {5},
pages = {719--730},
abstract = {DEAD-box RNA helicase DDX3 is a host factor essential for HIV-1 replication and thus, a potential target for novel therapies aimed to overcome viral resistance. Previous studies have shown that DDX3 promotes nuclear export and translation of the HIV-1 unspliced mRNA. Although the function of DDX3 during both processes requires its catalytic activity, it is unknown whether other domains surrounding the helicase core are involved. Here, we show the involvement of the N- and C-terminal domains of DDX3 in the regulation of HIV-1 unspliced mRNA translation. Our results suggest that the intrinsically disordered N-terminal domain of DDX3 regulates its functions in translation by acting prior to the recruitment of the 43S pre-initiation complex onto the viral 5'-UTR. Interestingly, this regulation was conserved in HIV-2 and was dependent on the CRM1-dependent nuclear export pathway suggesting a role of the RNA helicase in interconnecting nuclear export with ribosome recruitment of the viral unspliced mRNA. This specific function of DDX3 during HIV gene expression could be exploited as an alternative target for pharmaceutical intervention.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
DEAD-box RNA helicase DDX3 is a host factor essential for HIV-1 replication and thus, a potential target for novel therapies aimed to overcome viral resistance. Previous studies have shown that DDX3 promotes nuclear export and translation of the HIV-1 unspliced mRNA. Although the function of DDX3 during both processes requires its catalytic activity, it is unknown whether other domains surrounding the helicase core are involved. Here, we show the involvement of the N- and C-terminal domains of DDX3 in the regulation of HIV-1 unspliced mRNA translation. Our results suggest that the intrinsically disordered N-terminal domain of DDX3 regulates its functions in translation by acting prior to the recruitment of the 43S pre-initiation complex onto the viral 5'-UTR. Interestingly, this regulation was conserved in HIV-2 and was dependent on the CRM1-dependent nuclear export pathway suggesting a role of the RNA helicase in interconnecting nuclear export with ribosome recruitment of the viral unspliced mRNA. This specific function of DDX3 during HIV gene expression could be exploited as an alternative target for pharmaceutical intervention.2015
Sage, Valerie Le; Cinti, Alessandro; Valiente-Echeverría, Fernando; Mouland, Andrew J
Proteomic analysis of HIV-1 Gag interacting partners using proximity-dependent biotinylation Journal Article
In: Virol J, vol. 12, pp. 138, 2015, ISSN: 1743-422X.
@article{pmid26362536,
title = {Proteomic analysis of HIV-1 Gag interacting partners using proximity-dependent biotinylation},
author = {Valerie Le Sage and Alessandro Cinti and Fernando Valiente-Echeverría and Andrew J Mouland},
doi = {10.1186/s12985-015-0365-6},
issn = {1743-422X},
year = {2015},
date = {2015-09-01},
journal = {Virol J},
volume = {12},
pages = {138},
abstract = {BACKGROUND: The human immunodeficiency virus type 1 (HIV-1) Gag polyprotein is necessary and sufficient to assemble non-infectious particles. Given that HIV-1 subverts many host proteins at all stages of its life cycle, it is essential to identify these interactions as potential targets for antiretroviral therapy.
FINDINGS: This work demonstrates the use of proximity-dependent biotin identification (BioID) of host proteins and complexes that are proximal to the N-terminal domains of the HIV-1 Gag polyprotein. Two of the hits identified in the BioID screen were validated by immunoprecipation and confirmed the interaction of DDX17 and RPS6 with HIV-1 Gag.
CONCLUSIONS: Our results show that BioID is both a successful and complementary method to screen for nearby interacting proteins of HIV-1 Gag during the replicative cycle in different cell lines.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: The human immunodeficiency virus type 1 (HIV-1) Gag polyprotein is necessary and sufficient to assemble non-infectious particles. Given that HIV-1 subverts many host proteins at all stages of its life cycle, it is essential to identify these interactions as potential targets for antiretroviral therapy.
FINDINGS: This work demonstrates the use of proximity-dependent biotin identification (BioID) of host proteins and complexes that are proximal to the N-terminal domains of the HIV-1 Gag polyprotein. Two of the hits identified in the BioID screen were validated by immunoprecipation and confirmed the interaction of DDX17 and RPS6 with HIV-1 Gag.
CONCLUSIONS: Our results show that BioID is both a successful and complementary method to screen for nearby interacting proteins of HIV-1 Gag during the replicative cycle in different cell lines. Valiente-Echeverría, Fernando; Hermoso, Marcela A; Soto-Rifo, Ricardo
RNA helicase DDX3: at the crossroad of viral replication and antiviral immunity Journal Article
In: Rev Med Virol, vol. 25, no. 5, pp. 286–299, 2015, ISSN: 1099-1654.
@article{pmid26174373,
title = {RNA helicase DDX3: at the crossroad of viral replication and antiviral immunity},
author = {Fernando Valiente-Echeverría and Marcela A Hermoso and Ricardo Soto-Rifo},
doi = {10.1002/rmv.1845},
issn = {1099-1654},
year = {2015},
date = {2015-09-01},
journal = {Rev Med Virol},
volume = {25},
number = {5},
pages = {286--299},
abstract = {Asp-Glu-Ala-Asp (DEAD)-box polypeptide 3, or DDX3, belongs to the DEAD-box family of ATP-dependent RNA helicases and is known to play different roles in RNA metabolism ranging from transcription to nuclear export, translation, and assembly of stress granules. In addition, there is growing evidence that DDX3 is a component of the innate immune response against viral infections. As such, DDX3 has been shown to play roles both upstream and downstream of I-kappa beta kinase ε (IKKε)/TANK-binding kinase 1, leading to IFN-β production. Interestingly, several RNA viruses, including human threats such as HIV-1 and hepatitis C virus, hijack DDX3 to accomplish various steps of their replication cycles. Thus, it seems that viruses have evolved to exploit DDX3's functions while threatening the innate immune response. Understanding this interesting dichotomy in DDX3 function will help us not only to improve our knowledge of virus-host interactions but also to develop novel antiviral drugs targeting the multifaceted roles of DDX3 in viral replication.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Asp-Glu-Ala-Asp (DEAD)-box polypeptide 3, or DDX3, belongs to the DEAD-box family of ATP-dependent RNA helicases and is known to play different roles in RNA metabolism ranging from transcription to nuclear export, translation, and assembly of stress granules. In addition, there is growing evidence that DDX3 is a component of the innate immune response against viral infections. As such, DDX3 has been shown to play roles both upstream and downstream of I-kappa beta kinase ε (IKKε)/TANK-binding kinase 1, leading to IFN-β production. Interestingly, several RNA viruses, including human threats such as HIV-1 and hepatitis C virus, hijack DDX3 to accomplish various steps of their replication cycles. Thus, it seems that viruses have evolved to exploit DDX3's functions while threatening the innate immune response. Understanding this interesting dichotomy in DDX3 function will help us not only to improve our knowledge of virus-host interactions but also to develop novel antiviral drugs targeting the multifaceted roles of DDX3 in viral replication.2014
Soto-Rifo, Ricardo; Valiente-Echeverria, Fernando; Rubilar, Paulina S; Garcia-de-Gracia, Francisco; Ricci, Emiliano P; Limousin, Taran; Décimo, Didier; Mouland, Andrew J; Ohlmann, Théophile
HIV-2 genomic RNA accumulates in stress granules in the absence of active translation Journal Article
In: Nucleic Acids Res, vol. 42, no. 20, pp. 12861–12875, 2014, ISSN: 1362-4962.
@article{pmid25352557,
title = {HIV-2 genomic RNA accumulates in stress granules in the absence of active translation},
author = {Ricardo Soto-Rifo and Fernando Valiente-Echeverria and Paulina S Rubilar and Francisco Garcia-de-Gracia and Emiliano P Ricci and Taran Limousin and Didier Décimo and Andrew J Mouland and Théophile Ohlmann},
doi = {10.1093/nar/gku1017},
issn = {1362-4962},
year = {2014},
date = {2014-11-01},
journal = {Nucleic Acids Res},
volume = {42},
number = {20},
pages = {12861--12875},
abstract = {During the post-transcriptional events of the HIV-2 replication cycle, the full-length unspliced genomic RNA (gRNA) is first used as an mRNA to synthesize Gag and Gag-Pol proteins and then packaged into progeny virions. However, the mechanisms responsible for the coordinate usage of the gRNA during these two mutually exclusive events are poorly understood. Here, we present evidence showing that HIV-2 expression induces stress granule assembly in cultured cells. This contrasts with HIV-1, which interferes with stress granules assembly even upon induced cellular stress. Moreover, we observed that the RNA-binding protein and stress granules assembly factor TIAR associates with the gRNA to form a TIAR-HIV-2 ribonucleoprotein (TH2RNP) complex localizing diffuse in the cytoplasm or aggregated in stress granules. Although the assembly of TH2RNP in stress granules did not require the binding of the Gag protein to the gRNA, we observed that increased levels of Gag promoted both translational arrest and stress granule assembly. Moreover, HIV-2 Gag also localizes to stress granules in the absence of a 'packageable' gRNA. Our results indicate that the HIV-2 gRNA is compartmentalized in stress granules in the absence of active translation prior to being selected for packaging by the Gag polyprotein.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
During the post-transcriptional events of the HIV-2 replication cycle, the full-length unspliced genomic RNA (gRNA) is first used as an mRNA to synthesize Gag and Gag-Pol proteins and then packaged into progeny virions. However, the mechanisms responsible for the coordinate usage of the gRNA during these two mutually exclusive events are poorly understood. Here, we present evidence showing that HIV-2 expression induces stress granule assembly in cultured cells. This contrasts with HIV-1, which interferes with stress granules assembly even upon induced cellular stress. Moreover, we observed that the RNA-binding protein and stress granules assembly factor TIAR associates with the gRNA to form a TIAR-HIV-2 ribonucleoprotein (TH2RNP) complex localizing diffuse in the cytoplasm or aggregated in stress granules. Although the assembly of TH2RNP in stress granules did not require the binding of the Gag protein to the gRNA, we observed that increased levels of Gag promoted both translational arrest and stress granule assembly. Moreover, HIV-2 Gag also localizes to stress granules in the absence of a 'packageable' gRNA. Our results indicate that the HIV-2 gRNA is compartmentalized in stress granules in the absence of active translation prior to being selected for packaging by the Gag polyprotein. Sage, Valerie Le; Mouland, Andrew J; Valiente-Echeverría, Fernando
Roles of HIV-1 capsid in viral replication and immune evasion Journal Article
In: Virus Res, vol. 193, pp. 116–129, 2014, ISSN: 1872-7492.
@article{pmid25036886,
title = {Roles of HIV-1 capsid in viral replication and immune evasion},
author = {Valerie Le Sage and Andrew J Mouland and Fernando Valiente-Echeverría},
doi = {10.1016/j.virusres.2014.07.010},
issn = {1872-7492},
year = {2014},
date = {2014-11-01},
journal = {Virus Res},
volume = {193},
pages = {116--129},
abstract = {The primary roles of the human immunodeficiency virus type 1 (HIV-1) capsid (CA) protein are to encapsidate and protect the viral RNA genome. It is becoming increasing apparent that HIV-1 CA is a multifunctional protein that acts early during infection to coordinate uncoating, reverse transcription, nuclear import of the pre-integration complex and integration of double stranded viral DNA into the host genome. Additionally, numerous recent studies indicate that CA is playing a crucial function in HIV-1 immune evasion. Here we summarize the current knowledge on HIV-1 CA and its interactions with the host cell to promote infection. The fact that CA engages in a number of different protein-protein interactions with the host makes it an interesting target for the development of new potent antiviral agents.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The primary roles of the human immunodeficiency virus type 1 (HIV-1) capsid (CA) protein are to encapsidate and protect the viral RNA genome. It is becoming increasing apparent that HIV-1 CA is a multifunctional protein that acts early during infection to coordinate uncoating, reverse transcription, nuclear import of the pre-integration complex and integration of double stranded viral DNA into the host genome. Additionally, numerous recent studies indicate that CA is playing a crucial function in HIV-1 immune evasion. Here we summarize the current knowledge on HIV-1 CA and its interactions with the host cell to promote infection. The fact that CA engages in a number of different protein-protein interactions with the host makes it an interesting target for the development of new potent antiviral agents. Valiente-Echeverría, Fernando; Melnychuk, Luca; Vyboh, Kishanda; Ajamian, Lara; Gallouzi, Imed-Eddine; Bernard, Nicole; Mouland, Andrew J
eEF2 and Ras-GAP SH3 domain-binding protein (G3BP1) modulate stress granule assembly during HIV-1 infection Journal Article
In: Nat Commun, vol. 5, pp. 4819, 2014, ISSN: 2041-1723.
@article{pmid25229650,
title = {eEF2 and Ras-GAP SH3 domain-binding protein (G3BP1) modulate stress granule assembly during HIV-1 infection},
author = {Fernando Valiente-Echeverría and Luca Melnychuk and Kishanda Vyboh and Lara Ajamian and Imed-Eddine Gallouzi and Nicole Bernard and Andrew J Mouland},
doi = {10.1038/ncomms5819},
issn = {2041-1723},
year = {2014},
date = {2014-09-01},
journal = {Nat Commun},
volume = {5},
pages = {4819},
abstract = {Stress granules (SG) are translationally silent sites of RNA triage induced by environmental stresses including viral infection. Here we show that HIV-1 Gag blocks SG assembly irrespective of eIF2α phosphorylation and even when SG assembly is forced by overexpression of Ras-GAP SH3 domain-binding protein (G3BP1) or TIAR. The overexposed loops in the amino-terminal capsid domain of Gag and host eukaryotic elongation factor 2 (eEF2) are found to be critical for the SG blockade via interaction. Moreover, cyclophilin A (CypA) stabilizes the Gag-eEF2 association. eEF2 depletion not only lifts the SG blockade but also results in impaired virus production and infectivity. Gag also disassembles preformed SGs by recruiting G3BP1, thereby displacing eEF2, revealing another unsuspected virus-host interaction involved in the HIV-1-imposed SG blockade. Understanding how HIV-1 counters anti-viral stress responses will lay the groundwork for new therapeutic strategies to bolster host cell immune defences against HIV-1 and other pathogens.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Stress granules (SG) are translationally silent sites of RNA triage induced by environmental stresses including viral infection. Here we show that HIV-1 Gag blocks SG assembly irrespective of eIF2α phosphorylation and even when SG assembly is forced by overexpression of Ras-GAP SH3 domain-binding protein (G3BP1) or TIAR. The overexposed loops in the amino-terminal capsid domain of Gag and host eukaryotic elongation factor 2 (eEF2) are found to be critical for the SG blockade via interaction. Moreover, cyclophilin A (CypA) stabilizes the Gag-eEF2 association. eEF2 depletion not only lifts the SG blockade but also results in impaired virus production and infectivity. Gag also disassembles preformed SGs by recruiting G3BP1, thereby displacing eEF2, revealing another unsuspected virus-host interaction involved in the HIV-1-imposed SG blockade. Understanding how HIV-1 counters anti-viral stress responses will lay the groundwork for new therapeutic strategies to bolster host cell immune defences against HIV-1 and other pathogens.2013
Gordon, Heather; Ajamian, Lara; Valiente-Echeverrìa, Fernando; Lévesque, Kathy; Rigby, William F; Mouland, Andrew J
Depletion of hnRNP A2/B1 overrides the nuclear retention of the HIV-1 genomic RNA Journal Article
In: RNA Biol, vol. 10, no. 11, pp. 1714–1725, 2013, ISSN: 1555-8584.
@article{pmid24157614,
title = {Depletion of hnRNP A2/B1 overrides the nuclear retention of the HIV-1 genomic RNA},
author = {Heather Gordon and Lara Ajamian and Fernando Valiente-Echeverrìa and Kathy Lévesque and William F Rigby and Andrew J Mouland},
doi = {10.4161/rna.26542},
issn = {1555-8584},
year = {2013},
date = {2013-11-01},
journal = {RNA Biol},
volume = {10},
number = {11},
pages = {1714--1725},
abstract = {hnRNP A2 is a cellular protein that is important for nucleocytoplasmic and cytosolic trafficking of the HIV-1 genomic RNA. Both hnRNP A2's interaction with HIV-1 RNA and its expression levels influence the activities of Rev in mediating nucleocytoplasmic export of the HIV-1 genomic RNA. While the lack of Rev expression during HIV-1 gene expression results in nuclear retention of HIV-1 genomic RNA, we show here by fluorescence in situ hybridization and fractionation studies that the genomic RNA translocates to the cytoplasm when hnRNP A2/B1 are depleted from cells. Polyribosome analyses revealed that the genomic RNA was shunted into a cytoplasmic, dense polyribosomal fraction. This fraction contained several RNA-binding proteins involved in viral gene expression and RNA trafficking but did not contain the translation initiation factor, eIF4G1. Amino acid incorporation into nascent polypeptides in this fraction was also greatly reduced, demonstrating that this fraction contains mRNAs that are poorly translated. These results demonstrate that hnRNP A2/B1 expression plays roles in the nuclear retention of the HIV-1 genomic RNA in the absence of Rev and in the release of the genomic RNA from translationally inactive, cytoplasmic RNP complexes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
hnRNP A2 is a cellular protein that is important for nucleocytoplasmic and cytosolic trafficking of the HIV-1 genomic RNA. Both hnRNP A2's interaction with HIV-1 RNA and its expression levels influence the activities of Rev in mediating nucleocytoplasmic export of the HIV-1 genomic RNA. While the lack of Rev expression during HIV-1 gene expression results in nuclear retention of HIV-1 genomic RNA, we show here by fluorescence in situ hybridization and fractionation studies that the genomic RNA translocates to the cytoplasm when hnRNP A2/B1 are depleted from cells. Polyribosome analyses revealed that the genomic RNA was shunted into a cytoplasmic, dense polyribosomal fraction. This fraction contained several RNA-binding proteins involved in viral gene expression and RNA trafficking but did not contain the translation initiation factor, eIF4G1. Amino acid incorporation into nascent polypeptides in this fraction was also greatly reduced, demonstrating that this fraction contains mRNAs that are poorly translated. These results demonstrate that hnRNP A2/B1 expression plays roles in the nuclear retention of the HIV-1 genomic RNA in the absence of Rev and in the release of the genomic RNA from translationally inactive, cytoplasmic RNP complexes.
2023
Méndez, Constanza; Peñaloza, Hernán F; Schultz, Bárbara M; Piña-Iturbe, Alejandro; Ríos, Mariana; Moreno-Tapia, Daniela; Pereira-Sánchez, Patricia; Leighton, Diane; Orellana, Claudia; Covarrubias, Consuelo; Gálvez, Nicolás M S; Soto, Jorge A; Duarte, Luisa F; Rivera-Pérez, Daniela; Vázquez, Yaneisi; Cabrera, Alex; Bustos, Sergio; Iturriaga, Carolina; Urzua, Marcela; Navarrete, María S; Rojas, Álvaro; Fasce, Rodrigo A; Fernández, Jorge; Mora, Judith; Ramírez, Eugenio; Gaete-Argel, Aracelly; Acevedo, Mónica; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo; Weiskopf, Daniela; Grifoni, Alba; Sette, Alessandro; Zeng, Gang; Meng, Weining; ; González-Aramundiz, José V; González, Pablo A; Abarca, Katia; Melo-González, Felipe; Bueno, Susan M; Kalergis, Alexis M
Humoral and cellular response induced by a second booster of an inactivated SARS-CoV-2 vaccine in adults Journal Article
In: EBioMedicine, vol. 91, pp. 104563, 2023, ISSN: 2352-3964.
@article{pmid37099842,
title = {Humoral and cellular response induced by a second booster of an inactivated SARS-CoV-2 vaccine in adults},
author = {Constanza Méndez and Hernán F Peñaloza and Bárbara M Schultz and Alejandro Piña-Iturbe and Mariana Ríos and Daniela Moreno-Tapia and Patricia Pereira-Sánchez and Diane Leighton and Claudia Orellana and Consuelo Covarrubias and Nicolás M S Gálvez and Jorge A Soto and Luisa F Duarte and Daniela Rivera-Pérez and Yaneisi Vázquez and Alex Cabrera and Sergio Bustos and Carolina Iturriaga and Marcela Urzua and María S Navarrete and Álvaro Rojas and Rodrigo A Fasce and Jorge Fernández and Judith Mora and Eugenio Ramírez and Aracelly Gaete-Argel and Mónica Acevedo and Fernando Valiente-Echeverría and Ricardo Soto-Rifo and Daniela Weiskopf and Alba Grifoni and Alessandro Sette and Gang Zeng and Weining Meng and and José V González-Aramundiz and Pablo A González and Katia Abarca and Felipe Melo-González and Susan M Bueno and Alexis M Kalergis},
doi = {10.1016/j.ebiom.2023.104563},
issn = {2352-3964},
year = {2023},
date = {2023-05-01},
journal = {EBioMedicine},
volume = {91},
pages = {104563},
abstract = {BACKGROUND: The Omicron variant has challenged the control of the COVID-19 pandemic due to its immuno-evasive properties. The administration of a booster dose of a SARS-CoV-2 vaccine showed positive effects in the immunogenicity against SARS-CoV-2, effect that is even enhanced after the administration of a second booster.
METHODS: During a phase-3 clinical trial, we evaluated the effect of a second booster of CoronaVac®, an inactivated vaccine administered 6 months after the first booster, in the neutralization of SARS-CoV-2 (n = 87). In parallel, cellular immunity (n = 45) was analyzed in stimulated peripheral mononuclear cells by flow cytometry and ELISPOT.
FINDINGS: Although a 2.5-fold increase in neutralization of the ancestral SARS-CoV-2 was observed after the second booster when compared with prior its administration (Geometric mean units p < 0.0001; Geometric mean titer p = 0.0002), a poor neutralization against the Omicron variant was detected. Additionally, the activation of specific CD4 T lymphocytes remained stable after the second booster and, importantly, equivalent activation of CD4 T lymphocytes against the Omicron variant and the ancestral SARS-CoV-2 were found.
INTERPRETATION: Although the neutralizing response against the Omicron variant after the second booster of CoronaVac® was slightly increased, these levels are far from those observed against the ancestral SARS-CoV-2 and could most likely fail to neutralize the virus. In contrast, a robust CD4T cell response may confer protection against the Omicron variant.
FUNDING: The Ministry of Health, Government of Chile, the Confederation of Production and Commerce, Chile and SINOVAC Biotech.NIHNIAID. The Millennium Institute on Immunology and Immunotherapy.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: The Omicron variant has challenged the control of the COVID-19 pandemic due to its immuno-evasive properties. The administration of a booster dose of a SARS-CoV-2 vaccine showed positive effects in the immunogenicity against SARS-CoV-2, effect that is even enhanced after the administration of a second booster.
METHODS: During a phase-3 clinical trial, we evaluated the effect of a second booster of CoronaVac®, an inactivated vaccine administered 6 months after the first booster, in the neutralization of SARS-CoV-2 (n = 87). In parallel, cellular immunity (n = 45) was analyzed in stimulated peripheral mononuclear cells by flow cytometry and ELISPOT.
FINDINGS: Although a 2.5-fold increase in neutralization of the ancestral SARS-CoV-2 was observed after the second booster when compared with prior its administration (Geometric mean units p < 0.0001; Geometric mean titer p = 0.0002), a poor neutralization against the Omicron variant was detected. Additionally, the activation of specific CD4 T lymphocytes remained stable after the second booster and, importantly, equivalent activation of CD4 T lymphocytes against the Omicron variant and the ancestral SARS-CoV-2 were found.
INTERPRETATION: Although the neutralizing response against the Omicron variant after the second booster of CoronaVac® was slightly increased, these levels are far from those observed against the ancestral SARS-CoV-2 and could most likely fail to neutralize the virus. In contrast, a robust CD4T cell response may confer protection against the Omicron variant.
FUNDING: The Ministry of Health, Government of Chile, the Confederation of Production and Commerce, Chile and SINOVAC Biotech.NIHNIAID. The Millennium Institute on Immunology and Immunotherapy.
METHODS: During a phase-3 clinical trial, we evaluated the effect of a second booster of CoronaVac®, an inactivated vaccine administered 6 months after the first booster, in the neutralization of SARS-CoV-2 (n = 87). In parallel, cellular immunity (n = 45) was analyzed in stimulated peripheral mononuclear cells by flow cytometry and ELISPOT.
FINDINGS: Although a 2.5-fold increase in neutralization of the ancestral SARS-CoV-2 was observed after the second booster when compared with prior its administration (Geometric mean units p < 0.0001; Geometric mean titer p = 0.0002), a poor neutralization against the Omicron variant was detected. Additionally, the activation of specific CD4 T lymphocytes remained stable after the second booster and, importantly, equivalent activation of CD4 T lymphocytes against the Omicron variant and the ancestral SARS-CoV-2 were found.
INTERPRETATION: Although the neutralizing response against the Omicron variant after the second booster of CoronaVac® was slightly increased, these levels are far from those observed against the ancestral SARS-CoV-2 and could most likely fail to neutralize the virus. In contrast, a robust CD4T cell response may confer protection against the Omicron variant.
FUNDING: The Ministry of Health, Government of Chile, the Confederation of Production and Commerce, Chile and SINOVAC Biotech.NIHNIAID. The Millennium Institute on Immunology and Immunotherapy.
Acevedo, Johanna; Acevedo, Mónica L; Gaete-Argel, Aracelly; Araos, Rafael; Gonzalez, Cecilia; Espinoza, Daniela; Rivas, Solange; Pizarro, Pablo; Jarpa, Stephan; Soto-Rifo, Ricardo; Jara, Alejandro; Valiente-Echeverría, Fernando
Neutralizing antibodies induced by homologous and heterologous boosters in CoronaVac vaccines in Chile Journal Article
In: Clin Microbiol Infect, vol. 29, no. 4, pp. 541.e1–541.e7, 2023, ISSN: 1469-0691.
@article{pmid36436704,
title = {Neutralizing antibodies induced by homologous and heterologous boosters in CoronaVac vaccines in Chile},
author = {Johanna Acevedo and Mónica L Acevedo and Aracelly Gaete-Argel and Rafael Araos and Cecilia Gonzalez and Daniela Espinoza and Solange Rivas and Pablo Pizarro and Stephan Jarpa and Ricardo Soto-Rifo and Alejandro Jara and Fernando Valiente-Echeverría},
doi = {10.1016/j.cmi.2022.11.017},
issn = {1469-0691},
year = {2023},
date = {2023-04-01},
journal = {Clin Microbiol Infect},
volume = {29},
number = {4},
pages = {541.e1--541.e7},
abstract = {OBJECTIVES: To determine the impact of a booster dose on the humoral response in individuals inoculated with a complete schedule of any SARS-CoV-2 vaccine, we evaluated the neutralizing antibody (NAb) titres of homologous or heterologous booster doses over a 90-days period in CoronaVac vaccinees from 3 centres in Santiago, Chile.
METHODS: Individuals previously inoculated with 2 doses of CoronaVac (N = 523) were recruited in the context of the REFUERZO clinical trial (NCT04992182) and received either placebo (N = 129), or a booster dose of CoronaVac (N = 134), BNT162b2 (N = 133), or ChAdOx1 (N = 127). Pseudovirus neutralizing antibody titres (pVNT) were determined at baseline (day 0) as well as at days 14, 30, 60, and 90 after booster dose administration.
RESULTS: Inoculating a booster dose increases the pVNTs titres at days 14 and 30 in all groups, (13.5- and 12.0-fold increase for the CoronaVac group; 247.0- and 212.3-fold increase for the BTN162b2 group; and 89.1- and 128.1-fold increase for ChAdOx1 at each time point, respectively) with a decline observed at days 60 and 90. However, although pVNTs remained significantly higher for the BTN162b2 and ChAdOx1 groups at days 60 and 90, NAb titres reached baseline levels in the CoronaVac group at 90 days after inoculation.
DISCUSSION: A single heterologous booster (BTN162b2 or ChAdOx1) in individuals who completed the CoronaVac primary series resulted in an important increase in NAb titres remaining significantly higher at least for 90 days. These data may directly impact middle- and low-income countries currently using CoronaVac as the main vaccination strategy.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
OBJECTIVES: To determine the impact of a booster dose on the humoral response in individuals inoculated with a complete schedule of any SARS-CoV-2 vaccine, we evaluated the neutralizing antibody (NAb) titres of homologous or heterologous booster doses over a 90-days period in CoronaVac vaccinees from 3 centres in Santiago, Chile.
METHODS: Individuals previously inoculated with 2 doses of CoronaVac (N = 523) were recruited in the context of the REFUERZO clinical trial (NCT04992182) and received either placebo (N = 129), or a booster dose of CoronaVac (N = 134), BNT162b2 (N = 133), or ChAdOx1 (N = 127). Pseudovirus neutralizing antibody titres (pVNT) were determined at baseline (day 0) as well as at days 14, 30, 60, and 90 after booster dose administration.
RESULTS: Inoculating a booster dose increases the pVNTs titres at days 14 and 30 in all groups, (13.5- and 12.0-fold increase for the CoronaVac group; 247.0- and 212.3-fold increase for the BTN162b2 group; and 89.1- and 128.1-fold increase for ChAdOx1 at each time point, respectively) with a decline observed at days 60 and 90. However, although pVNTs remained significantly higher for the BTN162b2 and ChAdOx1 groups at days 60 and 90, NAb titres reached baseline levels in the CoronaVac group at 90 days after inoculation.
DISCUSSION: A single heterologous booster (BTN162b2 or ChAdOx1) in individuals who completed the CoronaVac primary series resulted in an important increase in NAb titres remaining significantly higher at least for 90 days. These data may directly impact middle- and low-income countries currently using CoronaVac as the main vaccination strategy.
METHODS: Individuals previously inoculated with 2 doses of CoronaVac (N = 523) were recruited in the context of the REFUERZO clinical trial (NCT04992182) and received either placebo (N = 129), or a booster dose of CoronaVac (N = 134), BNT162b2 (N = 133), or ChAdOx1 (N = 127). Pseudovirus neutralizing antibody titres (pVNT) were determined at baseline (day 0) as well as at days 14, 30, 60, and 90 after booster dose administration.
RESULTS: Inoculating a booster dose increases the pVNTs titres at days 14 and 30 in all groups, (13.5- and 12.0-fold increase for the CoronaVac group; 247.0- and 212.3-fold increase for the BTN162b2 group; and 89.1- and 128.1-fold increase for ChAdOx1 at each time point, respectively) with a decline observed at days 60 and 90. However, although pVNTs remained significantly higher for the BTN162b2 and ChAdOx1 groups at days 60 and 90, NAb titres reached baseline levels in the CoronaVac group at 90 days after inoculation.
DISCUSSION: A single heterologous booster (BTN162b2 or ChAdOx1) in individuals who completed the CoronaVac primary series resulted in an important increase in NAb titres remaining significantly higher at least for 90 days. These data may directly impact middle- and low-income countries currently using CoronaVac as the main vaccination strategy.
Sauré, Denis; O'Ryan, Miguel; Torres, Juan Pablo; Zuñiga, Marcela; Soto-Rifo, Ricardo; Valiente-Echeverría, Fernando; Gaete-Argel, Aracelly; Neira, Ignasi; Saavedra, Vicente; Acevedo, Mónica L; Archila, Carmen; Acuña, Fernando; Rain, Manuel; Basso, Leonardo J
In: Lancet Microbe, vol. 4, no. 3, pp. e149–e158, 2023, ISSN: 2666-5247.
@article{pmid36716754,
title = {COVID-19 lateral flow IgG seropositivity and serum neutralising antibody responses after primary and booster vaccinations in Chile: a cross-sectional study},
author = {Denis Sauré and Miguel O'Ryan and Juan Pablo Torres and Marcela Zuñiga and Ricardo Soto-Rifo and Fernando Valiente-Echeverría and Aracelly Gaete-Argel and Ignasi Neira and Vicente Saavedra and Mónica L Acevedo and Carmen Archila and Fernando Acuña and Manuel Rain and Leonardo J Basso},
doi = {10.1016/S2666-5247(22)00290-7},
issn = {2666-5247},
year = {2023},
date = {2023-03-01},
journal = {Lancet Microbe},
volume = {4},
number = {3},
pages = {e149--e158},
abstract = {BACKGROUND: By June 30, 2022, 92·6% of the Chilean population older than 18 years had received a full primary SARS-CoV-2 vaccine series, mostly with CoronaVac (Sinovac Biotech), and 78·4% had received a booster dose, mostly heterologous with BNT162b2 (Pfizer-BioNTech) and ChAdOx1 (AstraZeneca). We previously reported national seroprevalence data from lateral flow testing of IgG SARS-CoV-2 antibodies up to 16 weeks after primary vaccination. Our aim here was to study IgG seropositivity dynamics up to 30 weeks after primary vaccination and, in CoronaVac recipients, up to 26 weeks after booster vaccination, and to establish the correlation between lateral flow tests and neutralising antibody titres.
METHODS: In this cross-sectional study, testing stations for SARS-CoV-2 IgG detection were selected and installed from March 12, 2021, in hotspots in 24 large Chilean cities, and were maintained until March 31, 2022. Individuals voluntarily approaching the testing stations were invited to perform a rapid lateral flow test via a finger prick and complete a questionnaire. Between Aug 12, 2021, and April 1, 2022, volunteers seeking medical care in the Mutual de Seguridad de la Cámara Chilena de la Construcción provided blood samples for lateral flow testing and neutralising antibody studies; inclusion criteria were age at least 18 years, history of complete primary vaccination series with CoronaVac, BNT162b2, or ChAdOx1, or no vaccine, and no previous COVID-19 diagnosis. We tested the difference in IgG positivity across time, and between primary and booster doses, in all eligible participants with complete records, controlling for age, gender, and comorbidities. We also assessed the predictive power of neutralising antibody titres and sociodemographic characteristics on the probability of IgG positive results using multivariable logistic regression.
FINDINGS: Of 107 220 individuals recruited at the testing stations, 101 070 were included in our analysis (59 862 [59·2%] women and 41 208 [40·8%] men). 65 902 (65·2%) received primary vaccination series with CoronaVac, 18 548 (18·4%) with BNT162b2, and 606 (0·6%) with ChAdOx1, and 16 014 (15·8%) received no vaccine. Among the 61 767 individuals with a complete primary vaccination series with CoronaVac, 608 (1·0%) received a CoronaVac booster, 10 095 (16·3%) received a BNT162b2 booster, and 5435 (8·8%) received a ChAdOx1 booster. After ChAdOx1 primary vaccination, seropositivity peaked at week 5 after the second dose, occurring in 13 (92·9%, 95% CI 79·4-100·0) of 14 individuals. In participants who received a complete CoronaVac primary series, the decline in seropositivity stabilised at week 18 after the second dose (86 [44·7%, 95% CI 41·8-47·7] of 1087 individuals), whereas after receiving BNT162b2, seropositivity declined slightly by week 25 after the second dose (161 [94·2%, 90·6-97·7] of 171). A lower proportion of individuals who received the CoronaVac primary series and a homologous booster were seropositive (279 [85·6%, 95% CI 81·8-89·4] of 326) by weeks 2-18 than those who received a BNT162b2 booster (7031 [98·6%, 98·4-98·9] of 7128) or a ChAdOx1 booster (2893 [98·0%, 97·5-98·5] of 2953). The correlation between IgG positivity and log of the infectious dose in 50% of neutralising antibodies was moderate, with a sensitivity of 81·4% (95% CI 76·3-86·6) and specificity of 92·5% (73·3-100·0).
INTERPRETATION: Dynamic monitoring of IgG positivity to SARS-CoV-2 can characterise antibody waning over time in the absence or presence of booster doses, providing relevant data for the design of vaccination strategies. The correlation between lateral flow test IgG titres and neutralising antibody concentrations suggests that they could be a quick and effective surveillance tool to measure protection against SARS-CoV-2.
FUNDING: Instituto Sistemas Complejos de Ingeniería, Subsecretaría de Redes Asistenciales, Ministry of Health, Chile, and Mutual de Seguridad de la Cámara Chilena de la Construcción.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: By June 30, 2022, 92·6% of the Chilean population older than 18 years had received a full primary SARS-CoV-2 vaccine series, mostly with CoronaVac (Sinovac Biotech), and 78·4% had received a booster dose, mostly heterologous with BNT162b2 (Pfizer-BioNTech) and ChAdOx1 (AstraZeneca). We previously reported national seroprevalence data from lateral flow testing of IgG SARS-CoV-2 antibodies up to 16 weeks after primary vaccination. Our aim here was to study IgG seropositivity dynamics up to 30 weeks after primary vaccination and, in CoronaVac recipients, up to 26 weeks after booster vaccination, and to establish the correlation between lateral flow tests and neutralising antibody titres.
METHODS: In this cross-sectional study, testing stations for SARS-CoV-2 IgG detection were selected and installed from March 12, 2021, in hotspots in 24 large Chilean cities, and were maintained until March 31, 2022. Individuals voluntarily approaching the testing stations were invited to perform a rapid lateral flow test via a finger prick and complete a questionnaire. Between Aug 12, 2021, and April 1, 2022, volunteers seeking medical care in the Mutual de Seguridad de la Cámara Chilena de la Construcción provided blood samples for lateral flow testing and neutralising antibody studies; inclusion criteria were age at least 18 years, history of complete primary vaccination series with CoronaVac, BNT162b2, or ChAdOx1, or no vaccine, and no previous COVID-19 diagnosis. We tested the difference in IgG positivity across time, and between primary and booster doses, in all eligible participants with complete records, controlling for age, gender, and comorbidities. We also assessed the predictive power of neutralising antibody titres and sociodemographic characteristics on the probability of IgG positive results using multivariable logistic regression.
FINDINGS: Of 107 220 individuals recruited at the testing stations, 101 070 were included in our analysis (59 862 [59·2%] women and 41 208 [40·8%] men). 65 902 (65·2%) received primary vaccination series with CoronaVac, 18 548 (18·4%) with BNT162b2, and 606 (0·6%) with ChAdOx1, and 16 014 (15·8%) received no vaccine. Among the 61 767 individuals with a complete primary vaccination series with CoronaVac, 608 (1·0%) received a CoronaVac booster, 10 095 (16·3%) received a BNT162b2 booster, and 5435 (8·8%) received a ChAdOx1 booster. After ChAdOx1 primary vaccination, seropositivity peaked at week 5 after the second dose, occurring in 13 (92·9%, 95% CI 79·4-100·0) of 14 individuals. In participants who received a complete CoronaVac primary series, the decline in seropositivity stabilised at week 18 after the second dose (86 [44·7%, 95% CI 41·8-47·7] of 1087 individuals), whereas after receiving BNT162b2, seropositivity declined slightly by week 25 after the second dose (161 [94·2%, 90·6-97·7] of 171). A lower proportion of individuals who received the CoronaVac primary series and a homologous booster were seropositive (279 [85·6%, 95% CI 81·8-89·4] of 326) by weeks 2-18 than those who received a BNT162b2 booster (7031 [98·6%, 98·4-98·9] of 7128) or a ChAdOx1 booster (2893 [98·0%, 97·5-98·5] of 2953). The correlation between IgG positivity and log of the infectious dose in 50% of neutralising antibodies was moderate, with a sensitivity of 81·4% (95% CI 76·3-86·6) and specificity of 92·5% (73·3-100·0).
INTERPRETATION: Dynamic monitoring of IgG positivity to SARS-CoV-2 can characterise antibody waning over time in the absence or presence of booster doses, providing relevant data for the design of vaccination strategies. The correlation between lateral flow test IgG titres and neutralising antibody concentrations suggests that they could be a quick and effective surveillance tool to measure protection against SARS-CoV-2.
FUNDING: Instituto Sistemas Complejos de Ingeniería, Subsecretaría de Redes Asistenciales, Ministry of Health, Chile, and Mutual de Seguridad de la Cámara Chilena de la Construcción.
METHODS: In this cross-sectional study, testing stations for SARS-CoV-2 IgG detection were selected and installed from March 12, 2021, in hotspots in 24 large Chilean cities, and were maintained until March 31, 2022. Individuals voluntarily approaching the testing stations were invited to perform a rapid lateral flow test via a finger prick and complete a questionnaire. Between Aug 12, 2021, and April 1, 2022, volunteers seeking medical care in the Mutual de Seguridad de la Cámara Chilena de la Construcción provided blood samples for lateral flow testing and neutralising antibody studies; inclusion criteria were age at least 18 years, history of complete primary vaccination series with CoronaVac, BNT162b2, or ChAdOx1, or no vaccine, and no previous COVID-19 diagnosis. We tested the difference in IgG positivity across time, and between primary and booster doses, in all eligible participants with complete records, controlling for age, gender, and comorbidities. We also assessed the predictive power of neutralising antibody titres and sociodemographic characteristics on the probability of IgG positive results using multivariable logistic regression.
FINDINGS: Of 107 220 individuals recruited at the testing stations, 101 070 were included in our analysis (59 862 [59·2%] women and 41 208 [40·8%] men). 65 902 (65·2%) received primary vaccination series with CoronaVac, 18 548 (18·4%) with BNT162b2, and 606 (0·6%) with ChAdOx1, and 16 014 (15·8%) received no vaccine. Among the 61 767 individuals with a complete primary vaccination series with CoronaVac, 608 (1·0%) received a CoronaVac booster, 10 095 (16·3%) received a BNT162b2 booster, and 5435 (8·8%) received a ChAdOx1 booster. After ChAdOx1 primary vaccination, seropositivity peaked at week 5 after the second dose, occurring in 13 (92·9%, 95% CI 79·4-100·0) of 14 individuals. In participants who received a complete CoronaVac primary series, the decline in seropositivity stabilised at week 18 after the second dose (86 [44·7%, 95% CI 41·8-47·7] of 1087 individuals), whereas after receiving BNT162b2, seropositivity declined slightly by week 25 after the second dose (161 [94·2%, 90·6-97·7] of 171). A lower proportion of individuals who received the CoronaVac primary series and a homologous booster were seropositive (279 [85·6%, 95% CI 81·8-89·4] of 326) by weeks 2-18 than those who received a BNT162b2 booster (7031 [98·6%, 98·4-98·9] of 7128) or a ChAdOx1 booster (2893 [98·0%, 97·5-98·5] of 2953). The correlation between IgG positivity and log of the infectious dose in 50% of neutralising antibodies was moderate, with a sensitivity of 81·4% (95% CI 76·3-86·6) and specificity of 92·5% (73·3-100·0).
INTERPRETATION: Dynamic monitoring of IgG positivity to SARS-CoV-2 can characterise antibody waning over time in the absence or presence of booster doses, providing relevant data for the design of vaccination strategies. The correlation between lateral flow test IgG titres and neutralising antibody concentrations suggests that they could be a quick and effective surveillance tool to measure protection against SARS-CoV-2.
FUNDING: Instituto Sistemas Complejos de Ingeniería, Subsecretaría de Redes Asistenciales, Ministry of Health, Chile, and Mutual de Seguridad de la Cámara Chilena de la Construcción.
Acevedo, Mónica L; Gaete-Argel, Aracelly; Alonso-Palomares, Luis; de Oca, Marco Montes; Bustamante, Andrés; Gaggero, Aldo; Paredes, Fabio; Cortes, Claudia P; Pantano, Sergio; Martínez-Valdebenito, Constanza; Angulo, Jenniffer; Corre, Nicole Le; Ferrés, Marcela; Navarrete, Marcelo A; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo
2023.
@{pmid36658398,
title = {Author Correction: Differential neutralizing antibody responses elicited by CoronaVac and BNT162b2 against SARS-CoV-2 Lambda in Chile},
author = {Mónica L Acevedo and Aracelly Gaete-Argel and Luis Alonso-Palomares and Marco Montes de Oca and Andrés Bustamante and Aldo Gaggero and Fabio Paredes and Claudia P Cortes and Sergio Pantano and Constanza Martínez-Valdebenito and Jenniffer Angulo and Nicole Le Corre and Marcela Ferrés and Marcelo A Navarrete and Fernando Valiente-Echeverría and Ricardo Soto-Rifo},
doi = {10.1038/s41564-023-01324-y},
issn = {2058-5276},
year = {2023},
date = {2023-02-01},
journal = {Nat Microbiol},
volume = {8},
number = {2},
pages = {360},
keywords = {},
pubstate = {published},
tppubtype = {}
}
Gaete-Argel, Aracelly; Saavedra-Alarcón, Vicente; Sauré, Denis; Alonso-Palomares, Luis; Acevedo, Mónica L; Alarcón, Marion; Bueno, Susan M; Kalergis, Alexis M; Soto-Rifo, Ricardo; Valiente-Echeverría, Fernando; Cortes, Claudia P
Impact of homologous and heterologous boosters in neutralizing antibodies titers against SARS-CoV-2 Omicron in solid-organ transplant recipients Journal Article
In: Front Immunol, vol. 14, pp. 1135478, 2023, ISSN: 1664-3224.
@article{pmid36999018,
title = {Impact of homologous and heterologous boosters in neutralizing antibodies titers against SARS-CoV-2 Omicron in solid-organ transplant recipients},
author = {Aracelly Gaete-Argel and Vicente Saavedra-Alarcón and Denis Sauré and Luis Alonso-Palomares and Mónica L Acevedo and Marion Alarcón and Susan M Bueno and Alexis M Kalergis and Ricardo Soto-Rifo and Fernando Valiente-Echeverría and Claudia P Cortes},
doi = {10.3389/fimmu.2023.1135478},
issn = {1664-3224},
year = {2023},
date = {2023-01-01},
journal = {Front Immunol},
volume = {14},
pages = {1135478},
abstract = {INTRODUCTION: Booster doses of SARS-CoV-2 vaccines improve seroconversion rates in solid organ transplant recipients (SOTRs) but the impact of homologous and heterologous booster doses in neutralizing antibody (NAb) titers and their ability to interfere with the variant of concern Omicron are not well studied.
METHODS: We designed a prospective, open-label, observational clinical cohort study. 45 participants received two doses of BNT162b2 or CoronaVac (21-day or 28-day intervals, respectively) followed by a first and second booster with BNT162b2 (5-month apart each) and we analyzed the neutralizing antibody titers against SARSCoV-2 D614G (B.1 lineage) and Omicron (BA.1 lineage).
RESULTS: Our results show that SOTRs receiving an initial two-dose scheme of CoronaVac or BNT162b2 generate lower NAbs titers against the ancestral variant of SARS-CoV-2 when compared with healthy controls. Although these NAb titers were further decreased against the SARS-CoV-2 Omicron, a single BNT162b2 booster in both groups was sufficient to increase NAb titers against the variant of concern. More importantly, this effect was only observed in those participants responding to the first two shots but not in those not responding to the initial vaccination scheme.
DISCUSSION: The data provided here demonstrate the importance of monitoring antibody responses in immunocompromised subjects when planning booster vaccination programs in this risk group.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
INTRODUCTION: Booster doses of SARS-CoV-2 vaccines improve seroconversion rates in solid organ transplant recipients (SOTRs) but the impact of homologous and heterologous booster doses in neutralizing antibody (NAb) titers and their ability to interfere with the variant of concern Omicron are not well studied.
METHODS: We designed a prospective, open-label, observational clinical cohort study. 45 participants received two doses of BNT162b2 or CoronaVac (21-day or 28-day intervals, respectively) followed by a first and second booster with BNT162b2 (5-month apart each) and we analyzed the neutralizing antibody titers against SARSCoV-2 D614G (B.1 lineage) and Omicron (BA.1 lineage).
RESULTS: Our results show that SOTRs receiving an initial two-dose scheme of CoronaVac or BNT162b2 generate lower NAbs titers against the ancestral variant of SARS-CoV-2 when compared with healthy controls. Although these NAb titers were further decreased against the SARS-CoV-2 Omicron, a single BNT162b2 booster in both groups was sufficient to increase NAb titers against the variant of concern. More importantly, this effect was only observed in those participants responding to the first two shots but not in those not responding to the initial vaccination scheme.
DISCUSSION: The data provided here demonstrate the importance of monitoring antibody responses in immunocompromised subjects when planning booster vaccination programs in this risk group.
METHODS: We designed a prospective, open-label, observational clinical cohort study. 45 participants received two doses of BNT162b2 or CoronaVac (21-day or 28-day intervals, respectively) followed by a first and second booster with BNT162b2 (5-month apart each) and we analyzed the neutralizing antibody titers against SARSCoV-2 D614G (B.1 lineage) and Omicron (BA.1 lineage).
RESULTS: Our results show that SOTRs receiving an initial two-dose scheme of CoronaVac or BNT162b2 generate lower NAbs titers against the ancestral variant of SARS-CoV-2 when compared with healthy controls. Although these NAb titers were further decreased against the SARS-CoV-2 Omicron, a single BNT162b2 booster in both groups was sufficient to increase NAb titers against the variant of concern. More importantly, this effect was only observed in those participants responding to the first two shots but not in those not responding to the initial vaccination scheme.
DISCUSSION: The data provided here demonstrate the importance of monitoring antibody responses in immunocompromised subjects when planning booster vaccination programs in this risk group.
2022
Soto, Jorge A; Melo-González, Felipe; Gutierrez-Vera, Cristián; Schultz, Bárbara M; Berríos-Rojas, Roslye V; Rivera-Pérez, Daniela; Piña-Iturbe, Alejandro; Hoppe-Elsholz, Guillermo; Duarte, Luisa F; Vázquez, Yaneisi; Moreno-Tapia, Daniela; Ríos, Mariana; Palacios, Pablo A; Garcia-Betancourt, Richard; Santibañez, Álvaro; Pacheco, Gaspar A; Mendez, Constanza; Andrade, Catalina A; Silva, Pedro H; Diethelm-Varela, Benjamín; Astudillo, Patricio; Calvo, Mario; Cárdenas, Antonio; González, Marcela; Goldsack, Macarena; Gutiérrez, Valentina; Potin, Marcela; Schilling, Andrea; Tapia, Lorena I; Twele, Loreto; Villena, Rodolfo; Grifoni, Alba; Sette, Alessandro; Weiskopf, Daniela; Fasce, Rodrigo A; Fernández, Jorge; Mora, Judith; Ramírez, Eugenio; Gaete-Argel, Aracelly; Acevedo, Mónica L; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo; Retamal-Díaz, Angello; Muñoz-Jofré, Nathalia; ; Meng, Xing; Xin, Qianqian; Alarcón-Bustamante, Eduardo; González-Aramundiz, José V; Corre, Nicole Le; Álvarez-Figueroa, María Javiera; González, Pablo A; Abarca, Katia; Perret, Cecilia; Carreño, Leandro J; Bueno, Susan M; Kalergis, Alexis M
Inactivated Vaccine-Induced SARS-CoV-2 Variant-Specific Immunity in Children Journal Article
In: mBio, vol. 13, no. 6, pp. e0131122, 2022, ISSN: 2150-7511.
@article{pmid36383021,
title = {Inactivated Vaccine-Induced SARS-CoV-2 Variant-Specific Immunity in Children},
author = {Jorge A Soto and Felipe Melo-González and Cristián Gutierrez-Vera and Bárbara M Schultz and Roslye V Berríos-Rojas and Daniela Rivera-Pérez and Alejandro Piña-Iturbe and Guillermo Hoppe-Elsholz and Luisa F Duarte and Yaneisi Vázquez and Daniela Moreno-Tapia and Mariana Ríos and Pablo A Palacios and Richard Garcia-Betancourt and Álvaro Santibañez and Gaspar A Pacheco and Constanza Mendez and Catalina A Andrade and Pedro H Silva and Benjamín Diethelm-Varela and Patricio Astudillo and Mario Calvo and Antonio Cárdenas and Marcela González and Macarena Goldsack and Valentina Gutiérrez and Marcela Potin and Andrea Schilling and Lorena I Tapia and Loreto Twele and Rodolfo Villena and Alba Grifoni and Alessandro Sette and Daniela Weiskopf and Rodrigo A Fasce and Jorge Fernández and Judith Mora and Eugenio Ramírez and Aracelly Gaete-Argel and Mónica L Acevedo and Fernando Valiente-Echeverría and Ricardo Soto-Rifo and Angello Retamal-Díaz and Nathalia Muñoz-Jofré and and Xing Meng and Qianqian Xin and Eduardo Alarcón-Bustamante and José V González-Aramundiz and Nicole Le Corre and María Javiera Álvarez-Figueroa and Pablo A González and Katia Abarca and Cecilia Perret and Leandro J Carreño and Susan M Bueno and Alexis M Kalergis},
doi = {10.1128/mbio.01311-22},
issn = {2150-7511},
year = {2022},
date = {2022-12-01},
journal = {mBio},
volume = {13},
number = {6},
pages = {e0131122},
abstract = {Multiple vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been evaluated in clinical trials. However, trials addressing the immune response in the pediatric population are scarce. The inactivated vaccine CoronaVac has been shown to be safe and immunogenic in a phase 1/2 clinical trial in a pediatric cohort in China. Here, we report interim safety and immunogenicity results of a phase 3 clinical trial for CoronaVac in healthy children and adolescents in Chile. Participants 3 to 17 years old received two doses of CoronaVac in a 4-week interval until 31 December 2021. Local and systemic adverse reactions were registered for volunteers who received one or two doses of CoronaVac. Whole-blood samples were collected from a subgroup of 148 participants for humoral and cellular immunity analyses. The main adverse reaction reported after the first and second doses was pain at the injection site. Four weeks after the second dose, an increase in neutralizing antibody titer was observed in subjects relative to their baseline visit. Similar results were found for activation of specific CD4 T cells. Neutralizing antibodies were identified against the Delta and Omicron variants. However, these titers were lower than those for the D614G strain. Importantly, comparable CD4 T cell responses were detected against these variants of concern. Therefore, CoronaVac is safe and immunogenic in subjects 3 to 17 years old, inducing neutralizing antibody secretion and activating CD4 T cells against SARS-CoV-2 and its variants. (This study has been registered at ClinicalTrials.gov under no. NCT04992260.) This work evaluated the immune response induced by two doses of CoronaVac separated by 4 weeks in healthy children and adolescents in Chile. To date, few studies have described the effects of CoronaVac in the pediatric population. Therefore, it is essential to generate knowledge regarding the protection of vaccines in this population. Along these lines, we reported the anti-S humoral response and cellular immune response to several SARS-CoV-2 proteins that have been published and recently studied. Here, we show that a vaccination schedule consisting of two doses separated by 4 weeks induces the secretion of neutralizing antibodies against SARS-CoV-2. Furthermore, CoronaVac induces the activation of CD4 T cells upon stimulation with peptides from the proteome of SARS-CoV-2. These results indicate that, even though the neutralizing antibody response induced by vaccination decreases against the Delta and Omicron variants, the cellular response against these variants is comparable to the response against the ancestral strain D614G, even being significantly higher against Omicron.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Multiple vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been evaluated in clinical trials. However, trials addressing the immune response in the pediatric population are scarce. The inactivated vaccine CoronaVac has been shown to be safe and immunogenic in a phase 1/2 clinical trial in a pediatric cohort in China. Here, we report interim safety and immunogenicity results of a phase 3 clinical trial for CoronaVac in healthy children and adolescents in Chile. Participants 3 to 17 years old received two doses of CoronaVac in a 4-week interval until 31 December 2021. Local and systemic adverse reactions were registered for volunteers who received one or two doses of CoronaVac. Whole-blood samples were collected from a subgroup of 148 participants for humoral and cellular immunity analyses. The main adverse reaction reported after the first and second doses was pain at the injection site. Four weeks after the second dose, an increase in neutralizing antibody titer was observed in subjects relative to their baseline visit. Similar results were found for activation of specific CD4 T cells. Neutralizing antibodies were identified against the Delta and Omicron variants. However, these titers were lower than those for the D614G strain. Importantly, comparable CD4 T cell responses were detected against these variants of concern. Therefore, CoronaVac is safe and immunogenic in subjects 3 to 17 years old, inducing neutralizing antibody secretion and activating CD4 T cells against SARS-CoV-2 and its variants. (This study has been registered at ClinicalTrials.gov under no. NCT04992260.) This work evaluated the immune response induced by two doses of CoronaVac separated by 4 weeks in healthy children and adolescents in Chile. To date, few studies have described the effects of CoronaVac in the pediatric population. Therefore, it is essential to generate knowledge regarding the protection of vaccines in this population. Along these lines, we reported the anti-S humoral response and cellular immune response to several SARS-CoV-2 proteins that have been published and recently studied. Here, we show that a vaccination schedule consisting of two doses separated by 4 weeks induces the secretion of neutralizing antibodies against SARS-CoV-2. Furthermore, CoronaVac induces the activation of CD4 T cells upon stimulation with peptides from the proteome of SARS-CoV-2. These results indicate that, even though the neutralizing antibody response induced by vaccination decreases against the Delta and Omicron variants, the cellular response against these variants is comparable to the response against the ancestral strain D614G, even being significantly higher against Omicron.
Gálvez, Nicolás M S; Pacheco, Gaspar A; Schultz, Bárbara M; Melo-González, Felipe; Soto, Jorge A; Duarte, Luisa F; González, Liliana A; Rivera-Pérez, Daniela; Ríos, Mariana; Berrios, Roslye V; Vázquez, Yaneisi; Moreno-Tapia, Daniela; Vallejos, Omar P; Andrade, Catalina A; Hoppe-Elsholz, Guillermo; Iturriaga, Carolina; Urzua, Marcela; Navarrete, María S; Rojas, Álvaro; Fasce, Rodrigo; Fernández, Jorge; Mora, Judith; Ramírez, Eugenio; Gaete-Argel, Aracelly; Acevedo, Mónica L; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo; Weiskopf, Daniela; Grifoni, Alba; Sette, Alessandro; Zeng, Gang; Meng, Weining; ; González-Aramundiz, José V; Johnson, Marina; Goldblatt, David; González, Pablo A; Abarca, Katia; Bueno, Susan M; Kalergis, Alexis M
In: Elife, vol. 11, 2022, ISSN: 2050-084X.
@article{pmid36226829,
title = {Differences in the immune response elicited by two immunization schedules with an inactivated SARS-CoV-2 vaccine in a randomized phase 3 clinical trial},
author = {Nicolás M S Gálvez and Gaspar A Pacheco and Bárbara M Schultz and Felipe Melo-González and Jorge A Soto and Luisa F Duarte and Liliana A González and Daniela Rivera-Pérez and Mariana Ríos and Roslye V Berrios and Yaneisi Vázquez and Daniela Moreno-Tapia and Omar P Vallejos and Catalina A Andrade and Guillermo Hoppe-Elsholz and Carolina Iturriaga and Marcela Urzua and María S Navarrete and Álvaro Rojas and Rodrigo Fasce and Jorge Fernández and Judith Mora and Eugenio Ramírez and Aracelly Gaete-Argel and Mónica L Acevedo and Fernando Valiente-Echeverría and Ricardo Soto-Rifo and Daniela Weiskopf and Alba Grifoni and Alessandro Sette and Gang Zeng and Weining Meng and and José V González-Aramundiz and Marina Johnson and David Goldblatt and Pablo A González and Katia Abarca and Susan M Bueno and Alexis M Kalergis},
doi = {10.7554/eLife.81477},
issn = {2050-084X},
year = {2022},
date = {2022-10-01},
journal = {Elife},
volume = {11},
abstract = {BACKGROUND: The development of vaccines to control the coronavirus disease 2019 (COVID-19) pandemic progression is a worldwide priority. CoronaVac is an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine approved for emergency use with robust efficacy and immunogenicity data reported in trials in China, Brazil, Indonesia, Turkey, and Chile.
METHODS: This study is a randomized, multicenter, and controlled phase 3 trial in healthy Chilean adults aged ≥18 years. Volunteers received two doses of CoronaVac separated by 2 (0-14 schedule) or 4 weeks (0-28 schedule); 2302 volunteers were enrolled, 440 were part of the immunogenicity arm, and blood samples were obtained at different times. Samples from a single center are reported. Humoral immune responses were evaluated by measuring the neutralizing capacities of circulating antibodies. Cellular immune responses were assessed by ELISPOT and flow cytometry. Correlation matrixes were performed to evaluate correlations in the data measured.
RESULTS: Both schedules exhibited robust neutralizing capacities with the response induced by the 0-28 schedule being better. No differences were found in the concentration of antibodies against the virus and different variants of concern (VOCs) between schedules. Stimulation of peripheral blood mononuclear cells (PBMCs) with Mega pools of Peptides (MPs) induced the secretion of interferon (IFN)-γ and the expression of activation induced markers in CD4 T cells for both schedules. Correlation matrixes showed strong correlations between neutralizing antibodies and IFN-γ secretion.
CONCLUSIONS: Immunization with CoronaVac in Chilean adults promotes robust cellular and humoral immune responses. The 0-28 schedule induced a stronger humoral immune response than the 0-14 schedule.
FUNDING: Ministry of Health, Government of Chile, Confederation of Production and Commerce & Millennium Institute on Immunology and Immunotherapy, Chile.
CLINICAL TRIAL NUMBER: NCT04651790.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: The development of vaccines to control the coronavirus disease 2019 (COVID-19) pandemic progression is a worldwide priority. CoronaVac is an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine approved for emergency use with robust efficacy and immunogenicity data reported in trials in China, Brazil, Indonesia, Turkey, and Chile.
METHODS: This study is a randomized, multicenter, and controlled phase 3 trial in healthy Chilean adults aged ≥18 years. Volunteers received two doses of CoronaVac separated by 2 (0-14 schedule) or 4 weeks (0-28 schedule); 2302 volunteers were enrolled, 440 were part of the immunogenicity arm, and blood samples were obtained at different times. Samples from a single center are reported. Humoral immune responses were evaluated by measuring the neutralizing capacities of circulating antibodies. Cellular immune responses were assessed by ELISPOT and flow cytometry. Correlation matrixes were performed to evaluate correlations in the data measured.
RESULTS: Both schedules exhibited robust neutralizing capacities with the response induced by the 0-28 schedule being better. No differences were found in the concentration of antibodies against the virus and different variants of concern (VOCs) between schedules. Stimulation of peripheral blood mononuclear cells (PBMCs) with Mega pools of Peptides (MPs) induced the secretion of interferon (IFN)-γ and the expression of activation induced markers in CD4 T cells for both schedules. Correlation matrixes showed strong correlations between neutralizing antibodies and IFN-γ secretion.
CONCLUSIONS: Immunization with CoronaVac in Chilean adults promotes robust cellular and humoral immune responses. The 0-28 schedule induced a stronger humoral immune response than the 0-14 schedule.
FUNDING: Ministry of Health, Government of Chile, Confederation of Production and Commerce & Millennium Institute on Immunology and Immunotherapy, Chile.
CLINICAL TRIAL NUMBER: NCT04651790.
METHODS: This study is a randomized, multicenter, and controlled phase 3 trial in healthy Chilean adults aged ≥18 years. Volunteers received two doses of CoronaVac separated by 2 (0-14 schedule) or 4 weeks (0-28 schedule); 2302 volunteers were enrolled, 440 were part of the immunogenicity arm, and blood samples were obtained at different times. Samples from a single center are reported. Humoral immune responses were evaluated by measuring the neutralizing capacities of circulating antibodies. Cellular immune responses were assessed by ELISPOT and flow cytometry. Correlation matrixes were performed to evaluate correlations in the data measured.
RESULTS: Both schedules exhibited robust neutralizing capacities with the response induced by the 0-28 schedule being better. No differences were found in the concentration of antibodies against the virus and different variants of concern (VOCs) between schedules. Stimulation of peripheral blood mononuclear cells (PBMCs) with Mega pools of Peptides (MPs) induced the secretion of interferon (IFN)-γ and the expression of activation induced markers in CD4 T cells for both schedules. Correlation matrixes showed strong correlations between neutralizing antibodies and IFN-γ secretion.
CONCLUSIONS: Immunization with CoronaVac in Chilean adults promotes robust cellular and humoral immune responses. The 0-28 schedule induced a stronger humoral immune response than the 0-14 schedule.
FUNDING: Ministry of Health, Government of Chile, Confederation of Production and Commerce & Millennium Institute on Immunology and Immunotherapy, Chile.
CLINICAL TRIAL NUMBER: NCT04651790.
Schultz, Bárbara M; Melo-González, Felipe; Duarte, Luisa F; Gálvez, Nicolás M S; Pacheco, Gaspar A; Soto, Jorge A; Berríos-Rojas, Roslye V; González, Liliana A; Moreno-Tapia, Daniela; Rivera-Pérez, Daniela; Ríos, Mariana; Vázquez, Yaneisi; Hoppe-Elsholz, Guillermo; Andrade-Parra, Catalina A; Vallejos, Omar P; Piña-Iturbe, Alejandro; Iturriaga, Carolina; Urzua, Marcela; Navarrete, María S; Rojas, Álvaro; Fasce, Rodrigo; Fernández, Jorge; Mora, Judith; Ramírez, Eugenio; Gaete-Argel, Aracelly; Acevedo, Mónica L; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo; Weiskopf, Daniela; Grifoni, Alba; Sette, Alessandro; Zeng, Gang; Meng, Weining; ; González-Aramundiz, José V; González, Pablo A; Abarca, Katia; Kalergis, Alexis M; Bueno, Susan M
A Booster Dose of CoronaVac Increases Neutralizing Antibodies and T Cells that Recognize Delta and Omicron Variants of Concern Journal Article
In: mBio, vol. 13, no. 4, pp. e0142322, 2022, ISSN: 2150-7511.
@article{pmid35946814,
title = {A Booster Dose of CoronaVac Increases Neutralizing Antibodies and T Cells that Recognize Delta and Omicron Variants of Concern},
author = {Bárbara M Schultz and Felipe Melo-González and Luisa F Duarte and Nicolás M S Gálvez and Gaspar A Pacheco and Jorge A Soto and Roslye V Berríos-Rojas and Liliana A González and Daniela Moreno-Tapia and Daniela Rivera-Pérez and Mariana Ríos and Yaneisi Vázquez and Guillermo Hoppe-Elsholz and Catalina A Andrade-Parra and Omar P Vallejos and Alejandro Piña-Iturbe and Carolina Iturriaga and Marcela Urzua and María S Navarrete and Álvaro Rojas and Rodrigo Fasce and Jorge Fernández and Judith Mora and Eugenio Ramírez and Aracelly Gaete-Argel and Mónica L Acevedo and Fernando Valiente-Echeverría and Ricardo Soto-Rifo and Daniela Weiskopf and Alba Grifoni and Alessandro Sette and Gang Zeng and Weining Meng and and José V González-Aramundiz and Pablo A González and Katia Abarca and Alexis M Kalergis and Susan M Bueno},
doi = {10.1128/mbio.01423-22},
issn = {2150-7511},
year = {2022},
date = {2022-08-01},
journal = {mBio},
volume = {13},
number = {4},
pages = {e0142322},
abstract = {CoronaVac is an inactivated SARS-CoV-2 vaccine approved by the World Health Organization (WHO). Previous studies reported increased levels of neutralizing antibodies and specific T cells 2 and 4 weeks after two doses of CoronaVac; these levels were significantly reduced at 6 to 8 months after the two doses. Here, we report the effect of a booster dose of CoronaVac on the anti-SARS-CoV-2 immune response generated against the variants of concern (VOCs), Delta and Omicron, in adults participating in a phase III clinical trial in Chile. Volunteers immunized with two doses of CoronaVac in a 4-week interval received a booster dose of the same vaccine between 24 and 30 weeks after the second dose. Neutralization capacities and T cell activation against VOCs Delta and Omicron were assessed 4 weeks after the booster dose. We observed a significant increase in neutralizing antibodies 4 weeks after the booster dose. We also observed a rise in anti-SARS-CoV-2-specific CD4 T cells over time, and these cells reached a peak 4 weeks after the booster dose. Furthermore, neutralizing antibodies and SARS-CoV-2-specific T cells induced by the booster showed activity against VOCs Delta and Omicron. Our results show that a booster dose of CoronaVac increases adults' humoral and cellular anti-SARS-CoV-2 immune responses. In addition, immunity induced by a booster dose of CoronaVac is active against VOCs, suggesting adequate protection. CoronaVac is an inactivated vaccine against SARS-CoV-2 that has been approved by WHO for emergency use. Phase III clinical trials are in progress in several countries, including China, Brazil, Turkey, and Chile, and have shown safety and immunogenicity after two doses of the vaccine. This report characterizes immune responses induced by two doses of CoronaVac followed by a booster dose 5 months after the second dose in healthy Chilean adults. The data reported here show that a booster dose increased the immune responses against SARS-CoV-2, enhancing levels of neutralizing antibodies against the ancestral strain and VOCs. Similarly, anti-SARS-CoV-2 CD4 T cell responses were increased following the booster dose. In contrast, levels of gamma interferon secretion and T cell activation against the VOCs Delta and Omicron were not significantly different from those for the ancestral strain. Therefore, a third dose of CoronaVac in a homologous vaccination schedule improves its immunogenicity in healthy volunteers.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
CoronaVac is an inactivated SARS-CoV-2 vaccine approved by the World Health Organization (WHO). Previous studies reported increased levels of neutralizing antibodies and specific T cells 2 and 4 weeks after two doses of CoronaVac; these levels were significantly reduced at 6 to 8 months after the two doses. Here, we report the effect of a booster dose of CoronaVac on the anti-SARS-CoV-2 immune response generated against the variants of concern (VOCs), Delta and Omicron, in adults participating in a phase III clinical trial in Chile. Volunteers immunized with two doses of CoronaVac in a 4-week interval received a booster dose of the same vaccine between 24 and 30 weeks after the second dose. Neutralization capacities and T cell activation against VOCs Delta and Omicron were assessed 4 weeks after the booster dose. We observed a significant increase in neutralizing antibodies 4 weeks after the booster dose. We also observed a rise in anti-SARS-CoV-2-specific CD4 T cells over time, and these cells reached a peak 4 weeks after the booster dose. Furthermore, neutralizing antibodies and SARS-CoV-2-specific T cells induced by the booster showed activity against VOCs Delta and Omicron. Our results show that a booster dose of CoronaVac increases adults' humoral and cellular anti-SARS-CoV-2 immune responses. In addition, immunity induced by a booster dose of CoronaVac is active against VOCs, suggesting adequate protection. CoronaVac is an inactivated vaccine against SARS-CoV-2 that has been approved by WHO for emergency use. Phase III clinical trials are in progress in several countries, including China, Brazil, Turkey, and Chile, and have shown safety and immunogenicity after two doses of the vaccine. This report characterizes immune responses induced by two doses of CoronaVac followed by a booster dose 5 months after the second dose in healthy Chilean adults. The data reported here show that a booster dose increased the immune responses against SARS-CoV-2, enhancing levels of neutralizing antibodies against the ancestral strain and VOCs. Similarly, anti-SARS-CoV-2 CD4 T cell responses were increased following the booster dose. In contrast, levels of gamma interferon secretion and T cell activation against the VOCs Delta and Omicron were not significantly different from those for the ancestral strain. Therefore, a third dose of CoronaVac in a homologous vaccination schedule improves its immunogenicity in healthy volunteers.
Bueno, Susan M; Abarca, Katia; González, Pablo A; Gálvez, Nicolás M S; Soto, Jorge A; Duarte, Luisa F; Schultz, Bárbara M; Pacheco, Gaspar A; González, Liliana A; Vázquez, Yaneisi; Ríos, Mariana; Melo-González, Felipe; Rivera-Pérez, Daniela; Iturriaga, Carolina; Urzúa, Marcela; Domínguez, Angélica; Andrade, Catalina A; Berríos-Rojas, Roslye V; Canedo-Marroquín, Gisela; Covián, Camila; Moreno-Tapia, Daniela; Saavedra, Farides; Vallejos, Omar P; Donato, Paulina; Espinoza, Pilar; Fuentes, Daniela; González, Marcela; Guzmán, Paula; Venturelli, Paula Muñoz; Pérez, Carlos M; Potin, Marcela; Rojas, Álvaro; Fasce, Rodrigo A; Fernández, Jorge; Mora, Judith; Ramírez, Eugenio; Gaete-Argel, Aracelly; Oyarzún-Arrau, Aarón; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo; Weiskopf, Daniela; Sette, Alessandro; Zeng, Gang; Meng, Weining; González-Aramundiz, José V; Kalergis, Alexis M
Safety and Immunogenicity of an Inactivated Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine in a Subgroup of Healthy Adults in Chile Journal Article
In: Clin Infect Dis, vol. 75, no. 1, pp. e792–e804, 2022, ISSN: 1537-6591.
@article{pmid34537835,
title = {Safety and Immunogenicity of an Inactivated Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine in a Subgroup of Healthy Adults in Chile},
author = {Susan M Bueno and Katia Abarca and Pablo A González and Nicolás M S Gálvez and Jorge A Soto and Luisa F Duarte and Bárbara M Schultz and Gaspar A Pacheco and Liliana A González and Yaneisi Vázquez and Mariana Ríos and Felipe Melo-González and Daniela Rivera-Pérez and Carolina Iturriaga and Marcela Urzúa and Angélica Domínguez and Catalina A Andrade and Roslye V Berríos-Rojas and Gisela Canedo-Marroquín and Camila Covián and Daniela Moreno-Tapia and Farides Saavedra and Omar P Vallejos and Paulina Donato and Pilar Espinoza and Daniela Fuentes and Marcela González and Paula Guzmán and Paula Muñoz Venturelli and Carlos M Pérez and Marcela Potin and Álvaro Rojas and Rodrigo A Fasce and Jorge Fernández and Judith Mora and Eugenio Ramírez and Aracelly Gaete-Argel and Aarón Oyarzún-Arrau and Fernando Valiente-Echeverría and Ricardo Soto-Rifo and Daniela Weiskopf and Alessandro Sette and Gang Zeng and Weining Meng and José V González-Aramundiz and Alexis M Kalergis},
doi = {10.1093/cid/ciab823},
issn = {1537-6591},
year = {2022},
date = {2022-08-01},
journal = {Clin Infect Dis},
volume = {75},
number = {1},
pages = {e792--e804},
abstract = {BACKGROUND: The development of effective vaccines against coronavirus disease 2019 is a global priority. CoronaVac is an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine with promising safety and immunogenicity profiles. This article reports safety and immunogenicity results obtained for healthy Chilean adults aged ≥18 years in a phase 3 clinical trial.
METHODS: Volunteers randomly received 2 doses of CoronaVac or placebo, separated by 2 weeks. A total of 434 volunteers were enrolled, 397 aged 18-59 years and 37 aged ≥60 years. Solicited and unsolicited adverse reactions were registered from all volunteers. Blood samples were obtained from a subset of volunteers and analyzed for humoral and cellular measures of immunogenicity.
RESULTS: The primary adverse reaction in the 434 volunteers was pain at the injection site, with a higher incidence in the vaccine than in the placebo arm. Adverse reactions observed were mostly mild and local. No severe adverse events were reported. The humoral evaluation was performed on 81 volunteers. Seroconversion rates for specific anti-S1-receptor binding domain (RBD) immunoglobulin G (IgG) were 82.22% and 84.44% in the 18-59 year age group and 62.69% and 70.37% in the ≥60 year age group, 2 and 4 weeks after the second dose, respectively. A significant increase in circulating neutralizing antibodies was detected 2 and 4 weeks after the second dose. The cellular evaluation was performed on 47 volunteers. We detected a significant induction of T-cell responses characterized by the secretion of interferon-γ (IFN-γ) upon stimulation with Mega Pools of peptides from SARS-CoV-2.
CONCLUSIONS: Immunization with CoronaVac in a 0-14 schedule in Chilean adults aged ≥18 years is safe, induces anti-S1-RBD IgG with neutralizing capacity, activates T cells, and promotes the secretion of IFN-γ upon stimulation with SARS-CoV-2 antigens.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: The development of effective vaccines against coronavirus disease 2019 is a global priority. CoronaVac is an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine with promising safety and immunogenicity profiles. This article reports safety and immunogenicity results obtained for healthy Chilean adults aged ≥18 years in a phase 3 clinical trial.
METHODS: Volunteers randomly received 2 doses of CoronaVac or placebo, separated by 2 weeks. A total of 434 volunteers were enrolled, 397 aged 18-59 years and 37 aged ≥60 years. Solicited and unsolicited adverse reactions were registered from all volunteers. Blood samples were obtained from a subset of volunteers and analyzed for humoral and cellular measures of immunogenicity.
RESULTS: The primary adverse reaction in the 434 volunteers was pain at the injection site, with a higher incidence in the vaccine than in the placebo arm. Adverse reactions observed were mostly mild and local. No severe adverse events were reported. The humoral evaluation was performed on 81 volunteers. Seroconversion rates for specific anti-S1-receptor binding domain (RBD) immunoglobulin G (IgG) were 82.22% and 84.44% in the 18-59 year age group and 62.69% and 70.37% in the ≥60 year age group, 2 and 4 weeks after the second dose, respectively. A significant increase in circulating neutralizing antibodies was detected 2 and 4 weeks after the second dose. The cellular evaluation was performed on 47 volunteers. We detected a significant induction of T-cell responses characterized by the secretion of interferon-γ (IFN-γ) upon stimulation with Mega Pools of peptides from SARS-CoV-2.
CONCLUSIONS: Immunization with CoronaVac in a 0-14 schedule in Chilean adults aged ≥18 years is safe, induces anti-S1-RBD IgG with neutralizing capacity, activates T cells, and promotes the secretion of IFN-γ upon stimulation with SARS-CoV-2 antigens.
METHODS: Volunteers randomly received 2 doses of CoronaVac or placebo, separated by 2 weeks. A total of 434 volunteers were enrolled, 397 aged 18-59 years and 37 aged ≥60 years. Solicited and unsolicited adverse reactions were registered from all volunteers. Blood samples were obtained from a subset of volunteers and analyzed for humoral and cellular measures of immunogenicity.
RESULTS: The primary adverse reaction in the 434 volunteers was pain at the injection site, with a higher incidence in the vaccine than in the placebo arm. Adverse reactions observed were mostly mild and local. No severe adverse events were reported. The humoral evaluation was performed on 81 volunteers. Seroconversion rates for specific anti-S1-receptor binding domain (RBD) immunoglobulin G (IgG) were 82.22% and 84.44% in the 18-59 year age group and 62.69% and 70.37% in the ≥60 year age group, 2 and 4 weeks after the second dose, respectively. A significant increase in circulating neutralizing antibodies was detected 2 and 4 weeks after the second dose. The cellular evaluation was performed on 47 volunteers. We detected a significant induction of T-cell responses characterized by the secretion of interferon-γ (IFN-γ) upon stimulation with Mega Pools of peptides from SARS-CoV-2.
CONCLUSIONS: Immunization with CoronaVac in a 0-14 schedule in Chilean adults aged ≥18 years is safe, induces anti-S1-RBD IgG with neutralizing capacity, activates T cells, and promotes the secretion of IFN-γ upon stimulation with SARS-CoV-2 antigens.
Vargas, Leonardo; Valdivieso, Nicolás; Tempio, Fabián; Simon, Valeska; Sauma, Daniela; Valenzuela, Lucía; Beltrán, Caroll; Castillo-Delgado, Loriana; Contreras-Benavides, Ximena; Acevedo, Mónica L; Acevedo, Johanna; Gonzalez, Rafael I; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo; Rosemblatt, Mario; Lopez, Mercedes; Osorio, Fabiola; Bono, María Rosa
Serological study of CoronaVac vaccine and booster doses in Chile: immunogenicity and persistence of anti-SARS-CoV-2 spike antibodies Journal Article
In: BMC Med, vol. 20, no. 1, pp. 216, 2022, ISSN: 1741-7015.
@article{pmid35676738,
title = {Serological study of CoronaVac vaccine and booster doses in Chile: immunogenicity and persistence of anti-SARS-CoV-2 spike antibodies},
author = {Leonardo Vargas and Nicolás Valdivieso and Fabián Tempio and Valeska Simon and Daniela Sauma and Lucía Valenzuela and Caroll Beltrán and Loriana Castillo-Delgado and Ximena Contreras-Benavides and Mónica L Acevedo and Johanna Acevedo and Rafael I Gonzalez and Fernando Valiente-Echeverría and Ricardo Soto-Rifo and Mario Rosemblatt and Mercedes Lopez and Fabiola Osorio and María Rosa Bono},
doi = {10.1186/s12916-022-02406-0},
issn = {1741-7015},
year = {2022},
date = {2022-06-01},
journal = {BMC Med},
volume = {20},
number = {1},
pages = {216},
abstract = {BACKGROUND: Chile was severely affected by COVID19 outbreaks but was also one of the first countries to start a nationwide program to vaccinate against the disease. Furthermore, Chile became one of the fastest countries to inoculate a high percentage of the target population and implemented homologous and heterologous booster schemes in late 2021 to prevent potential immunological waning. The aim of this study is to compare the immunogenicity and time course of the humoral response elicited by the CoronaVac vaccine in combination with homologous versus heterologous boosters.
METHODS: We compared the immunogenicity of two doses of CoronaVac and BNT162b2 vaccines and one homologous or heterologous booster through an ELISA assay directed against the ancestral spike protein of SARS-CoV-2. Sera were collected from individuals during the vaccination schedule and throughout the implementation of homologous and heterologous booster programs in Chile.
RESULTS: Our findings demonstrate that a two-dose vaccination scheme with CoronaVac induces lower levels of anti-SARS-CoV-2 spike antibodies than BNT162b2 in a broad age range (median age 42 years; interquartile range (IQR) 27-61). Furthermore, antibody production declines with time in individuals vaccinated with CoronaVac and less noticeably, with BNT162b2. Analysis of booster schemes revealed that individuals vaccinated with two doses of CoronaVac generate immunological memory against the SARS-CoV-2 ancestral strain, which can be re-activated with homologous or heterologous (BNT162b2 and ChAdOx1) boosters. Nevertheless, the magnitude of the antibody response with the heterologous booster regime was considerably higher (induction fold BNT162b2: 11.2x; ChAdoX1; 12.4x; CoronaVac: 6.0x) than the responses induced by the homologous scheme. Both homologous and heterologous boosters induced persistent humoral responses (median 122 days, IQR (108-133)), although heterologous boosters remained superior in activating a humoral response after 100 days.
CONCLUSIONS: Two doses of CoronaVac induces antibody titers against the SARS-CoV-2 ancestral strain which are lower in magnitude than those induced by the BNT162b2 vaccine. However, the response induced by CoronaVac can be greatly potentiated with a heterologous booster scheme with BNT162b2 or ChAdOx1 vaccines. Furthermore, the heterologous and homologous booster regimes induce a durable antibody response which does not show signs of decay 3 months after the booster dose.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Chile was severely affected by COVID19 outbreaks but was also one of the first countries to start a nationwide program to vaccinate against the disease. Furthermore, Chile became one of the fastest countries to inoculate a high percentage of the target population and implemented homologous and heterologous booster schemes in late 2021 to prevent potential immunological waning. The aim of this study is to compare the immunogenicity and time course of the humoral response elicited by the CoronaVac vaccine in combination with homologous versus heterologous boosters.
METHODS: We compared the immunogenicity of two doses of CoronaVac and BNT162b2 vaccines and one homologous or heterologous booster through an ELISA assay directed against the ancestral spike protein of SARS-CoV-2. Sera were collected from individuals during the vaccination schedule and throughout the implementation of homologous and heterologous booster programs in Chile.
RESULTS: Our findings demonstrate that a two-dose vaccination scheme with CoronaVac induces lower levels of anti-SARS-CoV-2 spike antibodies than BNT162b2 in a broad age range (median age 42 years; interquartile range (IQR) 27-61). Furthermore, antibody production declines with time in individuals vaccinated with CoronaVac and less noticeably, with BNT162b2. Analysis of booster schemes revealed that individuals vaccinated with two doses of CoronaVac generate immunological memory against the SARS-CoV-2 ancestral strain, which can be re-activated with homologous or heterologous (BNT162b2 and ChAdOx1) boosters. Nevertheless, the magnitude of the antibody response with the heterologous booster regime was considerably higher (induction fold BNT162b2: 11.2x; ChAdoX1; 12.4x; CoronaVac: 6.0x) than the responses induced by the homologous scheme. Both homologous and heterologous boosters induced persistent humoral responses (median 122 days, IQR (108-133)), although heterologous boosters remained superior in activating a humoral response after 100 days.
CONCLUSIONS: Two doses of CoronaVac induces antibody titers against the SARS-CoV-2 ancestral strain which are lower in magnitude than those induced by the BNT162b2 vaccine. However, the response induced by CoronaVac can be greatly potentiated with a heterologous booster scheme with BNT162b2 or ChAdOx1 vaccines. Furthermore, the heterologous and homologous booster regimes induce a durable antibody response which does not show signs of decay 3 months after the booster dose.
METHODS: We compared the immunogenicity of two doses of CoronaVac and BNT162b2 vaccines and one homologous or heterologous booster through an ELISA assay directed against the ancestral spike protein of SARS-CoV-2. Sera were collected from individuals during the vaccination schedule and throughout the implementation of homologous and heterologous booster programs in Chile.
RESULTS: Our findings demonstrate that a two-dose vaccination scheme with CoronaVac induces lower levels of anti-SARS-CoV-2 spike antibodies than BNT162b2 in a broad age range (median age 42 years; interquartile range (IQR) 27-61). Furthermore, antibody production declines with time in individuals vaccinated with CoronaVac and less noticeably, with BNT162b2. Analysis of booster schemes revealed that individuals vaccinated with two doses of CoronaVac generate immunological memory against the SARS-CoV-2 ancestral strain, which can be re-activated with homologous or heterologous (BNT162b2 and ChAdOx1) boosters. Nevertheless, the magnitude of the antibody response with the heterologous booster regime was considerably higher (induction fold BNT162b2: 11.2x; ChAdoX1; 12.4x; CoronaVac: 6.0x) than the responses induced by the homologous scheme. Both homologous and heterologous boosters induced persistent humoral responses (median 122 days, IQR (108-133)), although heterologous boosters remained superior in activating a humoral response after 100 days.
CONCLUSIONS: Two doses of CoronaVac induces antibody titers against the SARS-CoV-2 ancestral strain which are lower in magnitude than those induced by the BNT162b2 vaccine. However, the response induced by CoronaVac can be greatly potentiated with a heterologous booster scheme with BNT162b2 or ChAdOx1 vaccines. Furthermore, the heterologous and homologous booster regimes induce a durable antibody response which does not show signs of decay 3 months after the booster dose.
Acevedo, Mónica L; Gaete-Argel, Aracelly; Alonso-Palomares, Luis; de Oca, Marco Montes; Bustamante, Andrés; Gaggero, Aldo; Paredes, Fabio; Cortes, Claudia P; Pantano, Sergio; Martínez-Valdebenito, Constanza; Angulo, Jenniffer; Corre, Nicole Le; Ferrés, Marcela; Navarrete, Marcelo A; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo
2022.
@{pmid35606424,
title = {Author Correction: Differential neutralizing antibody responses elicited by CoronaVac and BNT162b2 against SARS-CoV-2 Lambda in Chile},
author = {Mónica L Acevedo and Aracelly Gaete-Argel and Luis Alonso-Palomares and Marco Montes de Oca and Andrés Bustamante and Aldo Gaggero and Fabio Paredes and Claudia P Cortes and Sergio Pantano and Constanza Martínez-Valdebenito and Jenniffer Angulo and Nicole Le Corre and Marcela Ferrés and Marcelo A Navarrete and Fernando Valiente-Echeverría and Ricardo Soto-Rifo},
doi = {10.1038/s41564-022-01154-4},
issn = {2058-5276},
year = {2022},
date = {2022-06-01},
journal = {Nat Microbiol},
volume = {7},
number = {6},
pages = {929},
keywords = {},
pubstate = {published},
tppubtype = {}
}
Wolff, Marcelo J; Acevedo, Mónica L; Núñez, María Antonieta; Lafourcade, Mónica; Gaete-Argel, Aracelly; Soto-Rifo, Ricardo; Valiente-Echeverría, Fernando
Neutralizing antibody titers elicited by CoronaVac and BNT162b2 vaccines in health care workers with and without prior SARS-CoV-2 infection Journal Article
In: J Travel Med, vol. 29, no. 3, 2022, ISSN: 1708-8305.
@article{pmid35134229,
title = {Neutralizing antibody titers elicited by CoronaVac and BNT162b2 vaccines in health care workers with and without prior SARS-CoV-2 infection},
author = {Marcelo J Wolff and Mónica L Acevedo and María Antonieta Núñez and Mónica Lafourcade and Aracelly Gaete-Argel and Ricardo Soto-Rifo and Fernando Valiente-Echeverría},
doi = {10.1093/jtm/taac010},
issn = {1708-8305},
year = {2022},
date = {2022-05-01},
journal = {J Travel Med},
volume = {29},
number = {3},
abstract = {We report neutralizing antibody titers (NAbTs) elicited by CoronaVac and BNT162b2 vaccines in healthcare workers with and without prior SARS-CoV-2 infection using both a pseudotype-based assay and a commercial kit. NAbTs were higher for the mRNA vaccine and increased in all previously infected. Good correlation between both assays was found.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
We report neutralizing antibody titers (NAbTs) elicited by CoronaVac and BNT162b2 vaccines in healthcare workers with and without prior SARS-CoV-2 infection using both a pseudotype-based assay and a commercial kit. NAbTs were higher for the mRNA vaccine and increased in all previously infected. Good correlation between both assays was found.
Acevedo, Mónica L; Gaete-Argel, Aracelly; Alonso-Palomares, Luis; de Oca, Marco Montes; Bustamante, Andrés; Gaggero, Aldo; Paredes, Fabio; Cortes, Claudia P; Pantano, Sergio; Martínez-Valdebenito, Constanza; Angulo, Jenniffer; Corre, Nicole Le; Ferrés, Marcela; Navarrete, Marcelo A; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo
Differential neutralizing antibody responses elicited by CoronaVac and BNT162b2 against SARS-CoV-2 Lambda in Chile Journal Article
In: Nat Microbiol, vol. 7, no. 4, pp. 524–529, 2022, ISSN: 2058-5276.
@article{pmid35365787,
title = {Differential neutralizing antibody responses elicited by CoronaVac and BNT162b2 against SARS-CoV-2 Lambda in Chile},
author = {Mónica L Acevedo and Aracelly Gaete-Argel and Luis Alonso-Palomares and Marco Montes de Oca and Andrés Bustamante and Aldo Gaggero and Fabio Paredes and Claudia P Cortes and Sergio Pantano and Constanza Martínez-Valdebenito and Jenniffer Angulo and Nicole Le Corre and Marcela Ferrés and Marcelo A Navarrete and Fernando Valiente-Echeverría and Ricardo Soto-Rifo},
doi = {10.1038/s41564-022-01092-1},
issn = {2058-5276},
year = {2022},
date = {2022-04-01},
journal = {Nat Microbiol},
volume = {7},
number = {4},
pages = {524--529},
abstract = {SARS-CoV-2 variant Lambda was dominant in several South American countries, including Chile. To ascertain the efficacy of local vaccination efforts, we used pseudotyped viruses to characterize the neutralization capacity of antibodies elicited by CoronaVac (n = 53) and BNT162b2 (n = 56) in healthcare workers from Clínica Santa María and the Faculty of Medicine at Universidad de Chile, as well as in convalescent plasma from individuals infected during the first wave visiting the Hospital Clínico at Pontificia Universidad Católica (n = 30). We observed that BNT162b2 elicits higher neutralizing antibody titres than CoronaVac, with differences ranging from 7.4-fold for the ancestral spike (Wuhan-Hu-1) to 8.2-fold for the Lambda spike and 13-fold for the Delta spike. Compared with the ancestral virus, neutralization against D614G, Alpha, Gamma, Lambda and Delta variants was reduced by between 0.93- and 4.22-fold for CoronaVac, 1.04- and 2.38-fold for BNT162b2, and 1.26- and 2.67-fold for convalescent plasma. Comparative analyses among the spike structures of the different variants suggest that mutations in the spike protein from the Lambda variant, including the 246-252 deletion in an antigenic supersite at the N-terminal domain loop and L452Q/F490S within the receptor-binding domain, may account for immune escape. Interestingly, analyses using pseudotyped and whole viruses showed increased entry rates into HEK293T-ACE2 cells, but reduced replication rates in Vero-E6 cells for the Lambda variant when compared with the Alpha, Gamma and Delta variants. Our data show that inactivated virus and messenger RNA vaccines elicit different levels of neutralizing antibodies with different potency to neutralize SARS-CoV-2 variants, including the variant of interest Lambda.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
SARS-CoV-2 variant Lambda was dominant in several South American countries, including Chile. To ascertain the efficacy of local vaccination efforts, we used pseudotyped viruses to characterize the neutralization capacity of antibodies elicited by CoronaVac (n = 53) and BNT162b2 (n = 56) in healthcare workers from Clínica Santa María and the Faculty of Medicine at Universidad de Chile, as well as in convalescent plasma from individuals infected during the first wave visiting the Hospital Clínico at Pontificia Universidad Católica (n = 30). We observed that BNT162b2 elicits higher neutralizing antibody titres than CoronaVac, with differences ranging from 7.4-fold for the ancestral spike (Wuhan-Hu-1) to 8.2-fold for the Lambda spike and 13-fold for the Delta spike. Compared with the ancestral virus, neutralization against D614G, Alpha, Gamma, Lambda and Delta variants was reduced by between 0.93- and 4.22-fold for CoronaVac, 1.04- and 2.38-fold for BNT162b2, and 1.26- and 2.67-fold for convalescent plasma. Comparative analyses among the spike structures of the different variants suggest that mutations in the spike protein from the Lambda variant, including the 246-252 deletion in an antigenic supersite at the N-terminal domain loop and L452Q/F490S within the receptor-binding domain, may account for immune escape. Interestingly, analyses using pseudotyped and whole viruses showed increased entry rates into HEK293T-ACE2 cells, but reduced replication rates in Vero-E6 cells for the Lambda variant when compared with the Alpha, Gamma and Delta variants. Our data show that inactivated virus and messenger RNA vaccines elicit different levels of neutralizing antibodies with different potency to neutralize SARS-CoV-2 variants, including the variant of interest Lambda.
González-Maldonado, Pamela; Alvarenga, Nelson; Burgos-Edwards, Alberto; Flores-Giubi, Ma Eugenia; Barúa, Javier E; Romero-Rodríguez, Ma Cristina; Soto-Rifo, Ricardo; Valiente-Echeverría, Fernando; Langjahr, Patricia; Cantero-González, Guadalupe; Sotelo, Pablo H
Screening of Natural Products Inhibitors of SARS-CoV-2 Entry Journal Article
In: Molecules, vol. 27, no. 5, 2022, ISSN: 1420-3049.
@article{pmid35268843,
title = {Screening of Natural Products Inhibitors of SARS-CoV-2 Entry},
author = {Pamela González-Maldonado and Nelson Alvarenga and Alberto Burgos-Edwards and Ma Eugenia Flores-Giubi and Javier E Barúa and Ma Cristina Romero-Rodríguez and Ricardo Soto-Rifo and Fernando Valiente-Echeverría and Patricia Langjahr and Guadalupe Cantero-González and Pablo H Sotelo},
doi = {10.3390/molecules27051743},
issn = {1420-3049},
year = {2022},
date = {2022-03-01},
journal = {Molecules},
volume = {27},
number = {5},
abstract = {The COVID-19 pandemic has led to the search for new molecules with antiviral activity against SARS-CoV-2. The entry of the virus into the cell is one of the main targets for inhibiting SARS-CoV-2 infection. Natural products are an important source of new therapeutic alternatives against diseases. Pseudotyped viruses allow the study of SARS-CoV-2 viral entry inhibitors, and due to their simplicity, they allow the screening of a large number of antiviral candidates in Biosafety Level 2 facilities. We used pseudotyped HIV-1 with the D614G SARS-CoV-2 spike glycoprotein to test its ability to infect ACE2-expressing HEK 293T cells in the presence of diverse natural products, including 21 plant extracts, 7 essential oils, and 13 compounds from plants and fungi. The 50% cytotoxic concentration (CC) was evaluated using the resazurin method. From these analyses, we determined the inhibitory activity of the extract of , which had a half-maximal inhibitory concentration (IC) of 91.65 µg/mL, a CC of 693.5 µg/mL, and a selectivity index (SI) of 7.57, indicating its potential use as an inhibitor of SARS-CoV-2 entry. Moreover, our work indicates the usefulness of the pseudotyped-virus system in the screening of SARS-CoV-2 entry inhibitors.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The COVID-19 pandemic has led to the search for new molecules with antiviral activity against SARS-CoV-2. The entry of the virus into the cell is one of the main targets for inhibiting SARS-CoV-2 infection. Natural products are an important source of new therapeutic alternatives against diseases. Pseudotyped viruses allow the study of SARS-CoV-2 viral entry inhibitors, and due to their simplicity, they allow the screening of a large number of antiviral candidates in Biosafety Level 2 facilities. We used pseudotyped HIV-1 with the D614G SARS-CoV-2 spike glycoprotein to test its ability to infect ACE2-expressing HEK 293T cells in the presence of diverse natural products, including 21 plant extracts, 7 essential oils, and 13 compounds from plants and fungi. The 50% cytotoxic concentration (CC) was evaluated using the resazurin method. From these analyses, we determined the inhibitory activity of the extract of , which had a half-maximal inhibitory concentration (IC) of 91.65 µg/mL, a CC of 693.5 µg/mL, and a selectivity index (SI) of 7.57, indicating its potential use as an inhibitor of SARS-CoV-2 entry. Moreover, our work indicates the usefulness of the pseudotyped-virus system in the screening of SARS-CoV-2 entry inhibitors.
Schultz, Bárbara M; Melo-González, Felipe; Duarte, Luisa F; Gálvez, Nicolás Ms; Pacheco, Gaspar A; Soto, Jorge A; Berríos-Rojas, Roslye V; González, Liliana A; Moreno-Tapia, Daniela; Rivera-Pérez, Daniela; Ríos, Mariana; Vázquez, Yaneisi; Hoppe-Elsholz, Guillermo; Vallejos, Omar P; Iturriaga, Carolina; Urzua, Marcela; Navarrete, María S; Rojas, Álvaro; Fasce, Rodrigo; Fernández, Jorge; Mora, Judith; Ramírez, Eugenio; Gaete-Argel, Aracelly; Acevedo, Mónica; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo; Weiskopf, Daniela; Grifoni, Alba; Sette, Alessandro; Zeng, Gang; Meng, Weining; ; González-Aramundiz, José V; González, Pablo A; Abarca, Katia; Kalergis, Alexis M; Bueno, Susan M
2022.
@{pmid35441179,
title = {A booster dose of an inactivated SARS-CoV-2 vaccine increases neutralizing antibodies and T cells that recognize Delta and Omicron variants of concern},
author = {Bárbara M Schultz and Felipe Melo-González and Luisa F Duarte and Nicolás Ms Gálvez and Gaspar A Pacheco and Jorge A Soto and Roslye V Berríos-Rojas and Liliana A González and Daniela Moreno-Tapia and Daniela Rivera-Pérez and Mariana Ríos and Yaneisi Vázquez and Guillermo Hoppe-Elsholz and Omar P Vallejos and Carolina Iturriaga and Marcela Urzua and María S Navarrete and Álvaro Rojas and Rodrigo Fasce and Jorge Fernández and Judith Mora and Eugenio Ramírez and Aracelly Gaete-Argel and Mónica Acevedo and Fernando Valiente-Echeverría and Ricardo Soto-Rifo and Daniela Weiskopf and Alba Grifoni and Alessandro Sette and Gang Zeng and Weining Meng and and José V González-Aramundiz and Pablo A González and Katia Abarca and Alexis M Kalergis and Susan M Bueno},
doi = {10.1101/2021.11.16.21266350},
year = {2022},
date = {2022-02-01},
journal = {medRxiv},
abstract = {BACKGROUND: CoronaVac is an inactivated SARS-CoV-2 vaccine approved by the World Health Organization. Previous studies reported increased levels of neutralizing antibodies and specific T cells two- and four-weeks after two doses of CoronaVac , but the levels of neutralizing antibodies are reduced at six to eight months after two doses. Here we report the effect of a booster dose of CoronaVac on the anti-SARS-CoV-2 immune response generated against variants of concern (VOC) Delta and Omicron in adults participating in a phase 3 clinical trial in Chile.
METHODS: Volunteers immunized with two doses of CoronaVac in a four-week interval received a booster dose of the same vaccine between twenty-four and thirty weeks after the 2nd dose. Four weeks after the booster dose, neutralizing antibodies and T cell responses were measured. Neutralization capacities and T cell activation against VOC Delta and Omicron were detected at four weeks after the booster dose.
FINDINGS: We observed a significant increase in neutralizing antibodies at four weeks after the booster dose. We also observed an increase in CD4 T cells numbers over time, reaching a peak at four weeks after the booster dose. Furthermore, neutralizing antibodies and SARS-CoV-2 specific T cells induced by the booster showed activity against VOC Delta and Omicron.
INTERPRETATION: Our results show that a booster dose of CoronaVac increases the anti-SARS-CoV-2 humoral and cellular immune responses in adults. Immunity induced by a booster dose of CoronaVac is active against VOC, suggesting an effective protection.},
keywords = {},
pubstate = {published},
tppubtype = {}
}
BACKGROUND: CoronaVac is an inactivated SARS-CoV-2 vaccine approved by the World Health Organization. Previous studies reported increased levels of neutralizing antibodies and specific T cells two- and four-weeks after two doses of CoronaVac , but the levels of neutralizing antibodies are reduced at six to eight months after two doses. Here we report the effect of a booster dose of CoronaVac on the anti-SARS-CoV-2 immune response generated against variants of concern (VOC) Delta and Omicron in adults participating in a phase 3 clinical trial in Chile.
METHODS: Volunteers immunized with two doses of CoronaVac in a four-week interval received a booster dose of the same vaccine between twenty-four and thirty weeks after the 2nd dose. Four weeks after the booster dose, neutralizing antibodies and T cell responses were measured. Neutralization capacities and T cell activation against VOC Delta and Omicron were detected at four weeks after the booster dose.
FINDINGS: We observed a significant increase in neutralizing antibodies at four weeks after the booster dose. We also observed an increase in CD4 T cells numbers over time, reaching a peak at four weeks after the booster dose. Furthermore, neutralizing antibodies and SARS-CoV-2 specific T cells induced by the booster showed activity against VOC Delta and Omicron.
INTERPRETATION: Our results show that a booster dose of CoronaVac increases the anti-SARS-CoV-2 humoral and cellular immune responses in adults. Immunity induced by a booster dose of CoronaVac is active against VOC, suggesting an effective protection.
METHODS: Volunteers immunized with two doses of CoronaVac in a four-week interval received a booster dose of the same vaccine between twenty-four and thirty weeks after the 2nd dose. Four weeks after the booster dose, neutralizing antibodies and T cell responses were measured. Neutralization capacities and T cell activation against VOC Delta and Omicron were detected at four weeks after the booster dose.
FINDINGS: We observed a significant increase in neutralizing antibodies at four weeks after the booster dose. We also observed an increase in CD4 T cells numbers over time, reaching a peak at four weeks after the booster dose. Furthermore, neutralizing antibodies and SARS-CoV-2 specific T cells induced by the booster showed activity against VOC Delta and Omicron.
INTERPRETATION: Our results show that a booster dose of CoronaVac increases the anti-SARS-CoV-2 humoral and cellular immune responses in adults. Immunity induced by a booster dose of CoronaVac is active against VOC, suggesting an effective protection.
Pereira-Montecinos, Camila; Toro-Ascuy, Daniela; Ananías-Sáez, Catarina; Gaete-Argel, Aracelly; Rojas-Fuentes, Cecilia; Riquelme-Barrios, Sebastián; Rojas-Araya, Bárbara; García-de-Gracia, Francisco; Aguilera-Cortés, Paulina; Chnaiderman, Jonás; Acevedo, Mónica L; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo
Epitranscriptomic regulation of HIV-1 full-length RNA packaging Journal Article
In: Nucleic Acids Res, vol. 50, no. 4, pp. 2302–2318, 2022, ISSN: 1362-4962.
@article{pmid35137199,
title = {Epitranscriptomic regulation of HIV-1 full-length RNA packaging},
author = {Camila Pereira-Montecinos and Daniela Toro-Ascuy and Catarina Ananías-Sáez and Aracelly Gaete-Argel and Cecilia Rojas-Fuentes and Sebastián Riquelme-Barrios and Bárbara Rojas-Araya and Francisco García-de-Gracia and Paulina Aguilera-Cortés and Jonás Chnaiderman and Mónica L Acevedo and Fernando Valiente-Echeverría and Ricardo Soto-Rifo},
doi = {10.1093/nar/gkac062},
issn = {1362-4962},
year = {2022},
date = {2022-02-01},
journal = {Nucleic Acids Res},
volume = {50},
number = {4},
pages = {2302--2318},
abstract = {During retroviral replication, the full-length RNA serves both as mRNA and genomic RNA. However, the mechanisms by which the HIV-1 Gag protein selects the two RNA molecules that will be packaged into nascent virions remain poorly understood. Here, we demonstrate that deposition of N6-methyladenosine (m6A) regulates full-length RNA packaging. While m6A deposition by METTL3/METTL14 onto the full-length RNA was associated with increased Gag synthesis and reduced packaging, FTO-mediated demethylation promoted the incorporation of the full-length RNA into viral particles. Interestingly, HIV-1 Gag associates with the RNA demethylase FTO in the nucleus and contributes to full-length RNA demethylation. We further identified two highly conserved adenosines within the 5'-UTR that have a crucial functional role in m6A methylation and packaging of the full-length RNA. Together, our data propose a novel epitranscriptomic mechanism allowing the selection of the HIV-1 full-length RNA molecules that will be used as viral genomes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
During retroviral replication, the full-length RNA serves both as mRNA and genomic RNA. However, the mechanisms by which the HIV-1 Gag protein selects the two RNA molecules that will be packaged into nascent virions remain poorly understood. Here, we demonstrate that deposition of N6-methyladenosine (m6A) regulates full-length RNA packaging. While m6A deposition by METTL3/METTL14 onto the full-length RNA was associated with increased Gag synthesis and reduced packaging, FTO-mediated demethylation promoted the incorporation of the full-length RNA into viral particles. Interestingly, HIV-1 Gag associates with the RNA demethylase FTO in the nucleus and contributes to full-length RNA demethylation. We further identified two highly conserved adenosines within the 5'-UTR that have a crucial functional role in m6A methylation and packaging of the full-length RNA. Together, our data propose a novel epitranscriptomic mechanism allowing the selection of the HIV-1 full-length RNA molecules that will be used as viral genomes.
Fuentes-Villalobos, Francisco; Garrido, Jose L; Medina, Matías A; Zambrano, Nicole; Ross, Natalia; Bravo, Felipe; Gaete-Argel, Aracelly; Oyarzún-Arrau, Aarón; Amanat, Fatima; Soto-Rifo, Ricardo; Valiente-Echeverría, Fernando; Ocampo, Renato; Esveile, Christian; Ferreira, Leonila; Cabrera, Johanna; Torres, Vivianne; Rioseco, Maria L; Riquelme, Raúl; Barría, Sebastián; Alvarez, Raymond; Pinos, Yazmín; Krammer, Florian; Calvo, Mario; and, Maria I Barria
Sustained Antibody-Dependent NK Cell Functions in Mild COVID-19 Outpatients During Convalescence Journal Article
In: Front Immunol, vol. 13, pp. 796481, 2022, ISSN: 1664-3224.
@article{pmid35197972,
title = {Sustained Antibody-Dependent NK Cell Functions in Mild COVID-19 Outpatients During Convalescence},
author = {Francisco Fuentes-Villalobos and Jose L Garrido and Matías A Medina and Nicole Zambrano and Natalia Ross and Felipe Bravo and Aracelly Gaete-Argel and Aarón Oyarzún-Arrau and Fatima Amanat and Ricardo Soto-Rifo and Fernando Valiente-Echeverría and Renato Ocampo and Christian Esveile and Leonila Ferreira and Johanna Cabrera and Vivianne Torres and Maria L Rioseco and Raúl Riquelme and Sebastián Barría and Raymond Alvarez and Yazmín Pinos and Florian Krammer and Mario Calvo and Maria I Barria and },
doi = {10.3389/fimmu.2022.796481},
issn = {1664-3224},
year = {2022},
date = {2022-01-01},
journal = {Front Immunol},
volume = {13},
pages = {796481},
abstract = {The coronavirus disease 2019 (COVID19) pandemic has left researchers scrambling to identify the humoral immune correlates of protection from COVID-19. To date, the antibody mediated correlates of virus neutralization have been extensively studied. However, the extent that non-neutralizing functions contribute to anti-viral responses are ill defined. In this study, we profiled the anti-spike antibody subtype/subclass responses, along with neutralization and antibody-dependent natural killer cell functions in 83 blood samples collected between 4 and 201 days post-symptoms onset from a cohort of COVID-19 outpatients. We observed heterogeneous humoral responses against the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. Overall, anti-spike profiles were characterized by a rapid rise of IgA and sustained IgG titers. In addition, strong antibody-mediated natural killer effector responses correlated with milder disease and being female. While higher neutralization profiles were observed in males along with increased severity. These results give an insight into the underlying function of antibodies beyond neutralization and suggest that antibody-mediated natural killer cell activity is a key function of the humoral response against the SARS-CoV-2 spike protein.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The coronavirus disease 2019 (COVID19) pandemic has left researchers scrambling to identify the humoral immune correlates of protection from COVID-19. To date, the antibody mediated correlates of virus neutralization have been extensively studied. However, the extent that non-neutralizing functions contribute to anti-viral responses are ill defined. In this study, we profiled the anti-spike antibody subtype/subclass responses, along with neutralization and antibody-dependent natural killer cell functions in 83 blood samples collected between 4 and 201 days post-symptoms onset from a cohort of COVID-19 outpatients. We observed heterogeneous humoral responses against the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. Overall, anti-spike profiles were characterized by a rapid rise of IgA and sustained IgG titers. In addition, strong antibody-mediated natural killer effector responses correlated with milder disease and being female. While higher neutralization profiles were observed in males along with increased severity. These results give an insight into the underlying function of antibodies beyond neutralization and suggest that antibody-mediated natural killer cell activity is a key function of the humoral response against the SARS-CoV-2 spike protein.
2021
Alonso-Palomares, Luis A; Cáceres, C Joaquín; Tapia, Rodrigo; Aguilera-Cortés, Paulina; Valenzuela, Santiago; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo; Gaggero, Aldo; Barriga, Gonzalo P
Surveillance of seasonal respiratory viruses among Chilean patients during the COVID-19 pandemic Journal Article
In: Health Sci Rep, vol. 4, no. 4, pp. e433, 2021, ISSN: 2398-8835.
@article{pmid34849406,
title = {Surveillance of seasonal respiratory viruses among Chilean patients during the COVID-19 pandemic},
author = {Luis A Alonso-Palomares and C Joaquín Cáceres and Rodrigo Tapia and Paulina Aguilera-Cortés and Santiago Valenzuela and Fernando Valiente-Echeverría and Ricardo Soto-Rifo and Aldo Gaggero and Gonzalo P Barriga},
doi = {10.1002/hsr2.433},
issn = {2398-8835},
year = {2021},
date = {2021-12-01},
journal = {Health Sci Rep},
volume = {4},
number = {4},
pages = {e433},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Pietrantoni, Gianfranco; Gaete-Argel, Aracelly; Herrera-Rojo, Diego; Ibarra-Karmy, Rodrigo; Bustos, Fernando J; Valiente-Echeverría, Fernando; Arriagada, Gloria
Dynein Light-Chain Dynlrb2 Is Essential for Murine Leukemia Virus Traffic and Nuclear Entry Journal Article
In: J Virol, vol. 95, no. 15, pp. e0017021, 2021, ISSN: 1098-5514.
@article{pmid33980598,
title = {Dynein Light-Chain Dynlrb2 Is Essential for Murine Leukemia Virus Traffic and Nuclear Entry},
author = {Gianfranco Pietrantoni and Aracelly Gaete-Argel and Diego Herrera-Rojo and Rodrigo Ibarra-Karmy and Fernando J Bustos and Fernando Valiente-Echeverría and Gloria Arriagada},
doi = {10.1128/JVI.00170-21},
issn = {1098-5514},
year = {2021},
date = {2021-07-01},
journal = {J Virol},
volume = {95},
number = {15},
pages = {e0017021},
abstract = {Murine leukemia virus (MLV) requires the infected cell to divide to access the nucleus to integrate into the host genome. It has been determined that MLV uses the microtubule and actin network to reach the nucleus at the early stages of infection. Several studies have shown that viruses use the dynein motor protein associated with microtubules for their displacement. We have previously reported that dynein light-chain roadblock type 2 (Dynlrb2) knockdown significantly decreases MLV infection compared to nonsilenced cells, suggesting a functional association between this dynein light chain and MLV preintegration complex (PIC). In this study, we aimed to determine if the dynein complex Dynlrb2 subunit plays an essential role in the retrograde transport of MLV. For this, an MLV mutant containing the green fluorescent protein (GFP) fused to the viral protein p12 was used to assay the PIC localization and speed in cells in which the expression of Dynlrb2 was modulated. We found a significant decrease in the arrival of MLV PIC to the nucleus and a reduced net speed of MLV PICs when Dynlrb2 was knocked down. In contrast, an increase in nuclear localization was observed when Dynlrb2 was overexpressed. Our results suggest that Dynlrb2 plays an essential role in MLV retrograde transport. Different viruses use different components of cytoplasmic dynein complex to traffic to their replication site. We have found that murine leukemia virus (MLV) depends on dynein light-chain Dynlrb2 for infection, retrograde traffic, and nuclear entry. Our study provides new information regarding the molecular requirements for retrograde transport of MLV preintegration complex and demonstrates the essential role of Dynlrb2 in MLV infection.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Murine leukemia virus (MLV) requires the infected cell to divide to access the nucleus to integrate into the host genome. It has been determined that MLV uses the microtubule and actin network to reach the nucleus at the early stages of infection. Several studies have shown that viruses use the dynein motor protein associated with microtubules for their displacement. We have previously reported that dynein light-chain roadblock type 2 (Dynlrb2) knockdown significantly decreases MLV infection compared to nonsilenced cells, suggesting a functional association between this dynein light chain and MLV preintegration complex (PIC). In this study, we aimed to determine if the dynein complex Dynlrb2 subunit plays an essential role in the retrograde transport of MLV. For this, an MLV mutant containing the green fluorescent protein (GFP) fused to the viral protein p12 was used to assay the PIC localization and speed in cells in which the expression of Dynlrb2 was modulated. We found a significant decrease in the arrival of MLV PIC to the nucleus and a reduced net speed of MLV PICs when Dynlrb2 was knocked down. In contrast, an increase in nuclear localization was observed when Dynlrb2 was overexpressed. Our results suggest that Dynlrb2 plays an essential role in MLV retrograde transport. Different viruses use different components of cytoplasmic dynein complex to traffic to their replication site. We have found that murine leukemia virus (MLV) depends on dynein light-chain Dynlrb2 for infection, retrograde traffic, and nuclear entry. Our study provides new information regarding the molecular requirements for retrograde transport of MLV preintegration complex and demonstrates the essential role of Dynlrb2 in MLV infection.
Hernández-Díaz, Tomás; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo
RNA Helicase DDX3: A Double-Edged Sword for Viral Replication and Immune Signaling Journal Article
In: Microorganisms, vol. 9, no. 6, 2021, ISSN: 2076-2607.
@article{pmid34204859,
title = {RNA Helicase DDX3: A Double-Edged Sword for Viral Replication and Immune Signaling},
author = {Tomás Hernández-Díaz and Fernando Valiente-Echeverría and Ricardo Soto-Rifo},
doi = {10.3390/microorganisms9061206},
issn = {2076-2607},
year = {2021},
date = {2021-06-01},
journal = {Microorganisms},
volume = {9},
number = {6},
abstract = {DDX3 is a cellular ATP-dependent RNA helicase involved in different aspects of RNA metabolism ranging from transcription to translation and therefore, DDX3 participates in the regulation of key cellular processes including cell cycle progression, apoptosis, cancer and the antiviral immune response leading to type-I interferon production. DDX3 has also been described as an essential cellular factor for the replication of different viruses, including important human threats such HIV-1 or HCV, and different small molecules targeting DDX3 activity have been developed. Indeed, increasing evidence suggests that DDX3 can be considered not only a promising but also a viable target for anticancer and antiviral treatments. In this review, we summarize distinct functional aspects of DDX3 focusing on its participation as a double-edged sword in the host immune response and in the replication cycle of different viruses.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
DDX3 is a cellular ATP-dependent RNA helicase involved in different aspects of RNA metabolism ranging from transcription to translation and therefore, DDX3 participates in the regulation of key cellular processes including cell cycle progression, apoptosis, cancer and the antiviral immune response leading to type-I interferon production. DDX3 has also been described as an essential cellular factor for the replication of different viruses, including important human threats such HIV-1 or HCV, and different small molecules targeting DDX3 activity have been developed. Indeed, increasing evidence suggests that DDX3 can be considered not only a promising but also a viable target for anticancer and antiviral treatments. In this review, we summarize distinct functional aspects of DDX3 focusing on its participation as a double-edged sword in the host immune response and in the replication cycle of different viruses.
Peña, Mónica; Ampuero, Manuel; Garcés, Carlos; Gaggero, Aldo; García, Patricia; Velasquez, María Soledad; Luza, Ricardo; Alvarez, Pía; Paredes, Fabio; Acevedo, Johanna; Farfán, Mauricio J; Solari, Sandra; Soto-Rifo, Ricardo; Valiente-Echeverría, Fernando
Performance of SARS-CoV-2 rapid antigen test compared with real-time RT-PCR in asymptomatic individuals Journal Article
In: Int J Infect Dis, vol. 107, pp. 201–204, 2021, ISSN: 1878-3511.
@article{pmid33945868,
title = {Performance of SARS-CoV-2 rapid antigen test compared with real-time RT-PCR in asymptomatic individuals},
author = {Mónica Peña and Manuel Ampuero and Carlos Garcés and Aldo Gaggero and Patricia García and María Soledad Velasquez and Ricardo Luza and Pía Alvarez and Fabio Paredes and Johanna Acevedo and Mauricio J Farfán and Sandra Solari and Ricardo Soto-Rifo and Fernando Valiente-Echeverría},
doi = {10.1016/j.ijid.2021.04.087},
issn = {1878-3511},
year = {2021},
date = {2021-06-01},
journal = {Int J Infect Dis},
volume = {107},
pages = {201--204},
abstract = {Screening, testing and contact tracing plays a pivotal role in control of the COVID-19 pandemic. To enable this it is necessary to increase the testing capacity. This study compared a SARS-CoV-2 rapid antigen test (RAT) and RT-PCR in 842 asymptomatic individuals from Tarapacá, Chile. A sensitivity of 69.86%, specificity of 99.61%, PPV of 94.44% and NPP of 97.22% with Ct values (Ct > 27) that were significantly higher among individuals with false-negative RAT were reported. These results support the fact that RAT might have a significant impact on the identification of asymptomatic carriers in areas that lack suitable laboratories to perform SARS-CoV-2 real-time RT-PCR diagnostics, or the results take more than 24-48 h, as well as zones with high traffic of individuals such as border/customs, airports, interregional bus, train stations or in any mass testing campaign requiring rapid results.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Screening, testing and contact tracing plays a pivotal role in control of the COVID-19 pandemic. To enable this it is necessary to increase the testing capacity. This study compared a SARS-CoV-2 rapid antigen test (RAT) and RT-PCR in 842 asymptomatic individuals from Tarapacá, Chile. A sensitivity of 69.86%, specificity of 99.61%, PPV of 94.44% and NPP of 97.22% with Ct values (Ct > 27) that were significantly higher among individuals with false-negative RAT were reported. These results support the fact that RAT might have a significant impact on the identification of asymptomatic carriers in areas that lack suitable laboratories to perform SARS-CoV-2 real-time RT-PCR diagnostics, or the results take more than 24-48 h, as well as zones with high traffic of individuals such as border/customs, airports, interregional bus, train stations or in any mass testing campaign requiring rapid results.
García-de-Gracia, Francisco; Gaete-Argel, Aracelly; Riquelme-Barrios, Sebastián; Pereira-Montecinos, Camila; Rojas-Araya, Bárbara; Aguilera, Paulina; Oyarzún-Arrau, Aarón; Rojas-Fuentes, Cecilia; Acevedo, Mónica L; Chnaiderman, Jonás; Valiente-Echeverría, Fernando; Toro-Ascuy, Daniela; Soto-Rifo, Ricardo
CBP80/20-dependent translation initiation factor (CTIF) inhibits HIV-1 Gag synthesis by targeting the function of the viral protein Rev Journal Article
In: RNA Biol, vol. 18, no. 5, pp. 745–758, 2021, ISSN: 1555-8584.
@article{pmid33103564,
title = {CBP80/20-dependent translation initiation factor (CTIF) inhibits HIV-1 Gag synthesis by targeting the function of the viral protein Rev},
author = {Francisco García-de-Gracia and Aracelly Gaete-Argel and Sebastián Riquelme-Barrios and Camila Pereira-Montecinos and Bárbara Rojas-Araya and Paulina Aguilera and Aarón Oyarzún-Arrau and Cecilia Rojas-Fuentes and Mónica L Acevedo and Jonás Chnaiderman and Fernando Valiente-Echeverría and Daniela Toro-Ascuy and Ricardo Soto-Rifo},
doi = {10.1080/15476286.2020.1832375},
issn = {1555-8584},
year = {2021},
date = {2021-05-01},
journal = {RNA Biol},
volume = {18},
number = {5},
pages = {745--758},
abstract = {Translation initiation of the human immunodeficiency virus type-1 (HIV-1) full-length RNA has been shown to occur through cap-dependent and IRES-driven mechanisms. Previous studies suggested that the nuclear cap-binding complex (CBC) rather than eIF4E drives cap-dependent translation of the full-length RNA and we have recently reported that the CBC subunit CBP80 supports the function of the viral protein Rev during nuclear export and translation of this viral transcript. Ribosome recruitment during CBC-dependent translation of cellular mRNAs relies on the activity CBP80/20 translation initiation factor (CTIF), which bridges CBP80 and the 40S ribosomal subunit through interactions with eIF3g. Here, we report that CTIF inhibits HIV-1 and HIV-2 Gag synthesis from the full-length RNA. Our results indicate that CTIF associates with HIV-1 Rev through its N-terminal domain and is recruited onto the full-length RNA ribonucleoprotein complex in order to interfere with Gag synthesis. We also demonstrate that CTIF induces the cytoplasmic accumulation of Rev impeding the association of the viral protein with CBP80. We finally show that Rev interferes with the association of CTIF with CBP80 indicating that CTIF and Rev compete for the CBC subunit.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Translation initiation of the human immunodeficiency virus type-1 (HIV-1) full-length RNA has been shown to occur through cap-dependent and IRES-driven mechanisms. Previous studies suggested that the nuclear cap-binding complex (CBC) rather than eIF4E drives cap-dependent translation of the full-length RNA and we have recently reported that the CBC subunit CBP80 supports the function of the viral protein Rev during nuclear export and translation of this viral transcript. Ribosome recruitment during CBC-dependent translation of cellular mRNAs relies on the activity CBP80/20 translation initiation factor (CTIF), which bridges CBP80 and the 40S ribosomal subunit through interactions with eIF3g. Here, we report that CTIF inhibits HIV-1 and HIV-2 Gag synthesis from the full-length RNA. Our results indicate that CTIF associates with HIV-1 Rev through its N-terminal domain and is recruited onto the full-length RNA ribonucleoprotein complex in order to interfere with Gag synthesis. We also demonstrate that CTIF induces the cytoplasmic accumulation of Rev impeding the association of the viral protein with CBP80. We finally show that Rev interferes with the association of CTIF with CBP80 indicating that CTIF and Rev compete for the CBC subunit.
Bueno, Susan M; Abarca, Katia; González, Pablo A; Gálvez, Nicolás Ms; Soto, Jorge A; Duarte, Luisa F; Schultz, Bárbara M; Pacheco, Gaspar A; González, Liliana A; Vázquez, Yaneisi; Ríos, Mariana; Melo-González, Felipe; Rivera-Pérez, Daniela; Iturriaga, Carolina; Urzúa, Marcela; Dominguez, Angélica; Andrade, Catalina A; Berrios, Roslye V; Canedo-Marroquín, Gisela; Covián, Camila; Moreno-Tapia, Daniela; Saavedra, Farides; Vallejos, Omar P; Donato, Paulina; Espinoza, Pilar; Fuentes, Daniela; González, Marcela; Guzmán, Paula; Muñoz-Venturelli, Paula; Pérez, Carlos M; Potin, Marcela; Rojas, Alvaro; Fasce, Rodrigo; Fernández, Jorge; Mora, Judith; Ramírez, Eugenio; Gaete-Argel, Aracelly; Oyarzún-Arrau, Aarón; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo; Weiskopf, Daniela; Sette, Alessandro; Zeng, Gang; Meng, Weining; González-Aramundiz, José V; Kalergis, Alexis M
2021.
@{pmid35441164,
title = {Interim report: Safety and immunogenicity of an inactivated vaccine against SARS-CoV-2 in healthy chilean adults in a phase 3 clinical trial},
author = {Susan M Bueno and Katia Abarca and Pablo A González and Nicolás Ms Gálvez and Jorge A Soto and Luisa F Duarte and Bárbara M Schultz and Gaspar A Pacheco and Liliana A González and Yaneisi Vázquez and Mariana Ríos and Felipe Melo-González and Daniela Rivera-Pérez and Carolina Iturriaga and Marcela Urzúa and Angélica Dominguez and Catalina A Andrade and Roslye V Berrios and Gisela Canedo-Marroquín and Camila Covián and Daniela Moreno-Tapia and Farides Saavedra and Omar P Vallejos and Paulina Donato and Pilar Espinoza and Daniela Fuentes and Marcela González and Paula Guzmán and Paula Muñoz-Venturelli and Carlos M Pérez and Marcela Potin and Alvaro Rojas and Rodrigo Fasce and Jorge Fernández and Judith Mora and Eugenio Ramírez and Aracelly Gaete-Argel and Aarón Oyarzún-Arrau and Fernando Valiente-Echeverría and Ricardo Soto-Rifo and Daniela Weiskopf and Alessandro Sette and Gang Zeng and Weining Meng and José V González-Aramundiz and Alexis M Kalergis},
doi = {10.1101/2021.03.31.21254494},
year = {2021},
date = {2021-04-01},
journal = {medRxiv},
abstract = {BACKGROUND: The ongoing COVID-19 pandemic has had a significant impact worldwide, with an incommensurable social and economic burden. The rapid development of safe and protective vaccines against this disease is a global priority. CoronaVac is a vaccine prototype based on inactivated SARS-CoV-2, which has shown promising safety and immunogenicity profiles in pre-clinical studies and phase 1/2 trials in China. To this day, four phase 3 clinical trials are ongoing with CoronaVac in Brazil, Indonesia, Turkey, and Chile. This article reports the safety and immunogenicity results obtained in a subgroup of participants aged 18 years and older enrolled in the phase 3 Clinical Trial held in Chile.
METHODS: This is a multicenter phase 3 clinical trial. Healthcare workers aged 18 years and older were randomly assigned to receive two doses of CoronaVac or placebo separated by two weeks (0-14). We report preliminary safety results obtained for a subset of 434 participants, and antibody and cell-mediated immunity results obtained in a subset of participants assigned to the immunogenicity arm. The primary and secondary aims of the study include the evaluation of safety parameters and immunogenicity against SARS-CoV-2 after immunization, respectively. This trial is registered at clinicaltrials.gov ( NCT04651790 ).
FINDINGS: The recruitment of participants occurred between November 27 , 2020, until January 9 , 2021. 434 participants were enrolled, 397 were 18-59 years old, and 37 were ≥60 years old. Of these, 270 were immunized with CoronaVac, and the remaining 164 participants were inoculated with the corresponding placebo. The primary adverse reaction was pain at the injection site, with a higher incidence in the vaccine arm (55.6%) than in the placebo arm (40.0%). Moreover, the incidence of pain at the injection site in the 18-59 years old group was 58.4% as compared to 32.0% in the ≥60 years old group. The seroconversion rate for specific anti-S1-RBD IgG was 47.8% for the 18-59 years old group 14 days post immunization (p.i.) and 95.6% 28 and 42 days p.i. For the ≥60 years old group, the seroconversion rate was 18.1%, 100%, and 87.5% at 14, 28, and 42 days p.i., respectively. Importantly, we observed a 95.7% seroconversion rate in neutralizing antibodies for the 18-59 years old group 28 and 42 days p.i. The ≥60 years old group exhibited seroconversion rates of 90.0% and 100% at 28 and 42 days p.i. Interestingly, we did not observe a significant seroconversion rate of anti-N-SARS-CoV-2 IgG for the 18-59 years old group. For the participants ≥60 years old, a modest rate of seroconversion at 42 days p.i. was observed (37.5%). We observed a significant induction of a T cell response characterized by the secretion of IFN-γ upon stimulation with Mega Pools of peptides derived from SARS-CoV-2 proteins. No significant differences between the two age groups were observed for cell-mediated immunity.
INTERPRETATION: Immunization with CoronaVac in a 0-14 schedule in adults of 18 years and older in the Chilean population is safe and induces specific IgG production against the S1-RBD with neutralizing capacity, as well as the activation of T cells secreting IFN-γ, upon recognition of SARS-CoV-2 antigens.
FUNDING: Ministry of Health of the Chilean Government; Confederation of Production and Commerce, Chile; Consortium of Universities for Vaccines and Therapies against COVID-19, Chile; Millennium Institute on Immunology and Immunotherapy.},
keywords = {},
pubstate = {published},
tppubtype = {}
}
BACKGROUND: The ongoing COVID-19 pandemic has had a significant impact worldwide, with an incommensurable social and economic burden. The rapid development of safe and protective vaccines against this disease is a global priority. CoronaVac is a vaccine prototype based on inactivated SARS-CoV-2, which has shown promising safety and immunogenicity profiles in pre-clinical studies and phase 1/2 trials in China. To this day, four phase 3 clinical trials are ongoing with CoronaVac in Brazil, Indonesia, Turkey, and Chile. This article reports the safety and immunogenicity results obtained in a subgroup of participants aged 18 years and older enrolled in the phase 3 Clinical Trial held in Chile.
METHODS: This is a multicenter phase 3 clinical trial. Healthcare workers aged 18 years and older were randomly assigned to receive two doses of CoronaVac or placebo separated by two weeks (0-14). We report preliminary safety results obtained for a subset of 434 participants, and antibody and cell-mediated immunity results obtained in a subset of participants assigned to the immunogenicity arm. The primary and secondary aims of the study include the evaluation of safety parameters and immunogenicity against SARS-CoV-2 after immunization, respectively. This trial is registered at clinicaltrials.gov ( NCT04651790 ).
FINDINGS: The recruitment of participants occurred between November 27 , 2020, until January 9 , 2021. 434 participants were enrolled, 397 were 18-59 years old, and 37 were ≥60 years old. Of these, 270 were immunized with CoronaVac, and the remaining 164 participants were inoculated with the corresponding placebo. The primary adverse reaction was pain at the injection site, with a higher incidence in the vaccine arm (55.6%) than in the placebo arm (40.0%). Moreover, the incidence of pain at the injection site in the 18-59 years old group was 58.4% as compared to 32.0% in the ≥60 years old group. The seroconversion rate for specific anti-S1-RBD IgG was 47.8% for the 18-59 years old group 14 days post immunization (p.i.) and 95.6% 28 and 42 days p.i. For the ≥60 years old group, the seroconversion rate was 18.1%, 100%, and 87.5% at 14, 28, and 42 days p.i., respectively. Importantly, we observed a 95.7% seroconversion rate in neutralizing antibodies for the 18-59 years old group 28 and 42 days p.i. The ≥60 years old group exhibited seroconversion rates of 90.0% and 100% at 28 and 42 days p.i. Interestingly, we did not observe a significant seroconversion rate of anti-N-SARS-CoV-2 IgG for the 18-59 years old group. For the participants ≥60 years old, a modest rate of seroconversion at 42 days p.i. was observed (37.5%). We observed a significant induction of a T cell response characterized by the secretion of IFN-γ upon stimulation with Mega Pools of peptides derived from SARS-CoV-2 proteins. No significant differences between the two age groups were observed for cell-mediated immunity.
INTERPRETATION: Immunization with CoronaVac in a 0-14 schedule in adults of 18 years and older in the Chilean population is safe and induces specific IgG production against the S1-RBD with neutralizing capacity, as well as the activation of T cells secreting IFN-γ, upon recognition of SARS-CoV-2 antigens.
FUNDING: Ministry of Health of the Chilean Government; Confederation of Production and Commerce, Chile; Consortium of Universities for Vaccines and Therapies against COVID-19, Chile; Millennium Institute on Immunology and Immunotherapy.
METHODS: This is a multicenter phase 3 clinical trial. Healthcare workers aged 18 years and older were randomly assigned to receive two doses of CoronaVac or placebo separated by two weeks (0-14). We report preliminary safety results obtained for a subset of 434 participants, and antibody and cell-mediated immunity results obtained in a subset of participants assigned to the immunogenicity arm. The primary and secondary aims of the study include the evaluation of safety parameters and immunogenicity against SARS-CoV-2 after immunization, respectively. This trial is registered at clinicaltrials.gov ( NCT04651790 ).
FINDINGS: The recruitment of participants occurred between November 27 , 2020, until January 9 , 2021. 434 participants were enrolled, 397 were 18-59 years old, and 37 were ≥60 years old. Of these, 270 were immunized with CoronaVac, and the remaining 164 participants were inoculated with the corresponding placebo. The primary adverse reaction was pain at the injection site, with a higher incidence in the vaccine arm (55.6%) than in the placebo arm (40.0%). Moreover, the incidence of pain at the injection site in the 18-59 years old group was 58.4% as compared to 32.0% in the ≥60 years old group. The seroconversion rate for specific anti-S1-RBD IgG was 47.8% for the 18-59 years old group 14 days post immunization (p.i.) and 95.6% 28 and 42 days p.i. For the ≥60 years old group, the seroconversion rate was 18.1%, 100%, and 87.5% at 14, 28, and 42 days p.i., respectively. Importantly, we observed a 95.7% seroconversion rate in neutralizing antibodies for the 18-59 years old group 28 and 42 days p.i. The ≥60 years old group exhibited seroconversion rates of 90.0% and 100% at 28 and 42 days p.i. Interestingly, we did not observe a significant seroconversion rate of anti-N-SARS-CoV-2 IgG for the 18-59 years old group. For the participants ≥60 years old, a modest rate of seroconversion at 42 days p.i. was observed (37.5%). We observed a significant induction of a T cell response characterized by the secretion of IFN-γ upon stimulation with Mega Pools of peptides derived from SARS-CoV-2 proteins. No significant differences between the two age groups were observed for cell-mediated immunity.
INTERPRETATION: Immunization with CoronaVac in a 0-14 schedule in adults of 18 years and older in the Chilean population is safe and induces specific IgG production against the S1-RBD with neutralizing capacity, as well as the activation of T cells secreting IFN-γ, upon recognition of SARS-CoV-2 antigens.
FUNDING: Ministry of Health of the Chilean Government; Confederation of Production and Commerce, Chile; Consortium of Universities for Vaccines and Therapies against COVID-19, Chile; Millennium Institute on Immunology and Immunotherapy.
Balcells, María Elvira; Rojas, Luis; Corre, Nicole Le; Martínez-Valdebenito, Constanza; Ceballos, María Elena; Ferrés, Marcela; Chang, Mayling; Vizcaya, Cecilia; Mondaca, Sebastián; Huete, Álvaro; Castro, Ricardo; Sarmiento, Mauricio; Villarroel, Luis; Pizarro, Alejandra; Ross, Patricio; Santander, Jaime; Lara, Bárbara; Ferrada, Marcela; Vargas-Salas, Sergio; Beltrán-Pavez, Carolina; Soto-Rifo, Ricardo; Valiente-Echeverría, Fernando; Caglevic, Christian; Mahave, Mauricio; Selman, Carolina; Gazitúa, Raimundo; Briones, José Luis; Villarroel-Espindola, Franz; Balmaceda, Carlos; Espinoza, Manuel A; Pereira, Jaime; Nervi, Bruno
Early versus deferred anti-SARS-CoV-2 convalescent plasma in patients admitted for COVID-19: A randomized phase II clinical trial Journal Article
In: PLoS Med, vol. 18, no. 3, pp. e1003415, 2021, ISSN: 1549-1676.
@article{pmid33657114,
title = {Early versus deferred anti-SARS-CoV-2 convalescent plasma in patients admitted for COVID-19: A randomized phase II clinical trial},
author = {María Elvira Balcells and Luis Rojas and Nicole Le Corre and Constanza Martínez-Valdebenito and María Elena Ceballos and Marcela Ferrés and Mayling Chang and Cecilia Vizcaya and Sebastián Mondaca and Álvaro Huete and Ricardo Castro and Mauricio Sarmiento and Luis Villarroel and Alejandra Pizarro and Patricio Ross and Jaime Santander and Bárbara Lara and Marcela Ferrada and Sergio Vargas-Salas and Carolina Beltrán-Pavez and Ricardo Soto-Rifo and Fernando Valiente-Echeverría and Christian Caglevic and Mauricio Mahave and Carolina Selman and Raimundo Gazitúa and José Luis Briones and Franz Villarroel-Espindola and Carlos Balmaceda and Manuel A Espinoza and Jaime Pereira and Bruno Nervi},
doi = {10.1371/journal.pmed.1003415},
issn = {1549-1676},
year = {2021},
date = {2021-03-01},
journal = {PLoS Med},
volume = {18},
number = {3},
pages = {e1003415},
abstract = {BACKGROUND: Convalescent plasma (CP), despite limited evidence on its efficacy, is being widely used as a compassionate therapy for hospitalized patients with COVID-19. We aimed to evaluate the efficacy and safety of early CP therapy in COVID-19 progression.
METHODS AND FINDINGS: The study was an open-label, single-center randomized clinical trial performed in an academic medical center in Santiago, Chile, from May 10, 2020, to July 18, 2020, with final follow-up until August 17, 2020. The trial included patients hospitalized within the first 7 days of COVID-19 symptom onset, presenting risk factors for illness progression and not on mechanical ventilation. The intervention consisted of immediate CP (early plasma group) versus no CP unless developing prespecified criteria of deterioration (deferred plasma group). Additional standard treatment was allowed in both arms. The primary outcome was a composite of mechanical ventilation, hospitalization for >14 days, or death. The key secondary outcomes included time to respiratory failure, days of mechanical ventilation, hospital length of stay, mortality at 30 days, and SARS-CoV-2 real-time PCR clearance rate. Of 58 randomized patients (mean age, 65.8 years; 50% male), 57 (98.3%) completed the trial. A total of 13 (43.3%) participants from the deferred group received plasma based on clinical aggravation. We failed to find benefit in the primary outcome (32.1% versus 33.3%, odds ratio [OR] 0.95, 95% CI 0.32-2.84, p > 0.999) in the early versus deferred CP group. The in-hospital mortality rate was 17.9% versus 6.7% (OR 3.04, 95% CI 0.54-17.17 p = 0.246), mechanical ventilation 17.9% versus 6.7% (OR 3.04, 95% CI 0.54-17.17, p = 0.246), and prolonged hospitalization 21.4% versus 30.0% (OR 0.64, 95% CI, 0.19-2.10, p = 0.554) in the early versus deferred CP group, respectively. The viral clearance rate on day 3 (26% versus 8%, p = 0.204) and day 7 (38% versus 19%, p = 0.374) did not differ between groups. Two patients experienced serious adverse events within 6 hours after plasma transfusion. The main limitation of this study is the lack of statistical power to detect a smaller but clinically relevant therapeutic effect of CP, as well as not having confirmed neutralizing antibodies in donor before plasma infusion.
CONCLUSIONS: In the present study, we failed to find evidence of benefit in mortality, length of hospitalization, or mechanical ventilation requirement by immediate addition of CP therapy in the early stages of COVID-19 compared to its use only in case of patient deterioration.
TRIAL REGISTRATION: NCT04375098.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Convalescent plasma (CP), despite limited evidence on its efficacy, is being widely used as a compassionate therapy for hospitalized patients with COVID-19. We aimed to evaluate the efficacy and safety of early CP therapy in COVID-19 progression.
METHODS AND FINDINGS: The study was an open-label, single-center randomized clinical trial performed in an academic medical center in Santiago, Chile, from May 10, 2020, to July 18, 2020, with final follow-up until August 17, 2020. The trial included patients hospitalized within the first 7 days of COVID-19 symptom onset, presenting risk factors for illness progression and not on mechanical ventilation. The intervention consisted of immediate CP (early plasma group) versus no CP unless developing prespecified criteria of deterioration (deferred plasma group). Additional standard treatment was allowed in both arms. The primary outcome was a composite of mechanical ventilation, hospitalization for >14 days, or death. The key secondary outcomes included time to respiratory failure, days of mechanical ventilation, hospital length of stay, mortality at 30 days, and SARS-CoV-2 real-time PCR clearance rate. Of 58 randomized patients (mean age, 65.8 years; 50% male), 57 (98.3%) completed the trial. A total of 13 (43.3%) participants from the deferred group received plasma based on clinical aggravation. We failed to find benefit in the primary outcome (32.1% versus 33.3%, odds ratio [OR] 0.95, 95% CI 0.32-2.84, p > 0.999) in the early versus deferred CP group. The in-hospital mortality rate was 17.9% versus 6.7% (OR 3.04, 95% CI 0.54-17.17 p = 0.246), mechanical ventilation 17.9% versus 6.7% (OR 3.04, 95% CI 0.54-17.17, p = 0.246), and prolonged hospitalization 21.4% versus 30.0% (OR 0.64, 95% CI, 0.19-2.10, p = 0.554) in the early versus deferred CP group, respectively. The viral clearance rate on day 3 (26% versus 8%, p = 0.204) and day 7 (38% versus 19%, p = 0.374) did not differ between groups. Two patients experienced serious adverse events within 6 hours after plasma transfusion. The main limitation of this study is the lack of statistical power to detect a smaller but clinically relevant therapeutic effect of CP, as well as not having confirmed neutralizing antibodies in donor before plasma infusion.
CONCLUSIONS: In the present study, we failed to find evidence of benefit in mortality, length of hospitalization, or mechanical ventilation requirement by immediate addition of CP therapy in the early stages of COVID-19 compared to its use only in case of patient deterioration.
TRIAL REGISTRATION: NCT04375098.
METHODS AND FINDINGS: The study was an open-label, single-center randomized clinical trial performed in an academic medical center in Santiago, Chile, from May 10, 2020, to July 18, 2020, with final follow-up until August 17, 2020. The trial included patients hospitalized within the first 7 days of COVID-19 symptom onset, presenting risk factors for illness progression and not on mechanical ventilation. The intervention consisted of immediate CP (early plasma group) versus no CP unless developing prespecified criteria of deterioration (deferred plasma group). Additional standard treatment was allowed in both arms. The primary outcome was a composite of mechanical ventilation, hospitalization for >14 days, or death. The key secondary outcomes included time to respiratory failure, days of mechanical ventilation, hospital length of stay, mortality at 30 days, and SARS-CoV-2 real-time PCR clearance rate. Of 58 randomized patients (mean age, 65.8 years; 50% male), 57 (98.3%) completed the trial. A total of 13 (43.3%) participants from the deferred group received plasma based on clinical aggravation. We failed to find benefit in the primary outcome (32.1% versus 33.3%, odds ratio [OR] 0.95, 95% CI 0.32-2.84, p > 0.999) in the early versus deferred CP group. The in-hospital mortality rate was 17.9% versus 6.7% (OR 3.04, 95% CI 0.54-17.17 p = 0.246), mechanical ventilation 17.9% versus 6.7% (OR 3.04, 95% CI 0.54-17.17, p = 0.246), and prolonged hospitalization 21.4% versus 30.0% (OR 0.64, 95% CI, 0.19-2.10, p = 0.554) in the early versus deferred CP group, respectively. The viral clearance rate on day 3 (26% versus 8%, p = 0.204) and day 7 (38% versus 19%, p = 0.374) did not differ between groups. Two patients experienced serious adverse events within 6 hours after plasma transfusion. The main limitation of this study is the lack of statistical power to detect a smaller but clinically relevant therapeutic effect of CP, as well as not having confirmed neutralizing antibodies in donor before plasma infusion.
CONCLUSIONS: In the present study, we failed to find evidence of benefit in mortality, length of hospitalization, or mechanical ventilation requirement by immediate addition of CP therapy in the early stages of COVID-19 compared to its use only in case of patient deterioration.
TRIAL REGISTRATION: NCT04375098.
Beltrán-Pavez, Carolina; Riquelme-Barrios, Sebastián; Oyarzún-Arrau, Aarón; Gaete-Argel, Aracelly; González-Stegmaier, Roxana; Cereceda-Solis, Karina; Aguirre, Adam; Travisany, Dante; Palma-Vejares, Ricardo; Barriga, Gonzalo P; Gaggero, Aldo; Martínez-Valdebenito, Constanza; Corre, Nicole Le; Ferrés, Marcela; Balcells, María Elvira; Fernandez, Jorge; Ramírez, Eugenio; Villarroel, Franz; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo
Insights into neutralizing antibody responses in individuals exposed to SARS-CoV-2 in Chile Journal Article
In: Sci Adv, vol. 7, no. 7, 2021, ISSN: 2375-2548.
@article{pmid33579701,
title = {Insights into neutralizing antibody responses in individuals exposed to SARS-CoV-2 in Chile},
author = {Carolina Beltrán-Pavez and Sebastián Riquelme-Barrios and Aarón Oyarzún-Arrau and Aracelly Gaete-Argel and Roxana González-Stegmaier and Karina Cereceda-Solis and Adam Aguirre and Dante Travisany and Ricardo Palma-Vejares and Gonzalo P Barriga and Aldo Gaggero and Constanza Martínez-Valdebenito and Nicole Le Corre and Marcela Ferrés and María Elvira Balcells and Jorge Fernandez and Eugenio Ramírez and Franz Villarroel and Fernando Valiente-Echeverría and Ricardo Soto-Rifo},
doi = {10.1126/sciadv.abe6855},
issn = {2375-2548},
year = {2021},
date = {2021-02-01},
journal = {Sci Adv},
volume = {7},
number = {7},
abstract = {Chile has one of the worst numbers worldwide in terms of SARS-CoV-2 positive cases and COVID-19-related deaths per million inhabitants; thus, characterization of neutralizing antibody (NAb) responses in the general population is critical to understanding of immunity at the local level. Given our inability to perform massive classical neutralization assays due to the scarce availability of BSL-3 facilities in the country, we developed and fully characterized an HIV-based SARS-CoV-2 pseudotype, which was used in a 96-well plate format to investigate NAb responses in samples from individuals exposed to SARS-CoV-2 or treated with convalescent plasma. We also identified samples with decreased or enhanced neutralization activity against the D614G spike variant compared with the wild type, indicating the relevance of this variant in host immunity. The data presented here represent the first insights into NAb responses in individuals from Chile, serving as a guide for future studies in the country.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Chile has one of the worst numbers worldwide in terms of SARS-CoV-2 positive cases and COVID-19-related deaths per million inhabitants; thus, characterization of neutralizing antibody (NAb) responses in the general population is critical to understanding of immunity at the local level. Given our inability to perform massive classical neutralization assays due to the scarce availability of BSL-3 facilities in the country, we developed and fully characterized an HIV-based SARS-CoV-2 pseudotype, which was used in a 96-well plate format to investigate NAb responses in samples from individuals exposed to SARS-CoV-2 or treated with convalescent plasma. We also identified samples with decreased or enhanced neutralization activity against the D614G spike variant compared with the wild type, indicating the relevance of this variant in host immunity. The data presented here represent the first insights into NAb responses in individuals from Chile, serving as a guide for future studies in the country.
Escobar, Alejandro; Reyes-López, Felipe E; Acevedo, Mónica L; Alonso-Palomares, Luis; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo; Portillo, Hugo; Gatica, Jimena; Flores, Ivan; Nova-Lamperti, Estefanía; Barrera-Avalos, Carlos; Bono, María Rosa; Vargas, Leonardo; Simon, Valeska; Leiva-Salcedo, Elias; Vial, Cecilia; Hormazabal, Juan; Cortes, Lina Jimena; Valdés, Daniel; Sandino, Ana M; Imarai, Mónica; Acuña-Castillo, Claudio
Evaluation of the Immune Response Induced by CoronaVac 28-Day Schedule Vaccination in a Healthy Population Group Journal Article
In: Front Immunol, vol. 12, pp. 766278, 2021, ISSN: 1664-3224.
@article{pmid35173705,
title = {Evaluation of the Immune Response Induced by CoronaVac 28-Day Schedule Vaccination in a Healthy Population Group},
author = {Alejandro Escobar and Felipe E Reyes-López and Mónica L Acevedo and Luis Alonso-Palomares and Fernando Valiente-Echeverría and Ricardo Soto-Rifo and Hugo Portillo and Jimena Gatica and Ivan Flores and Estefanía Nova-Lamperti and Carlos Barrera-Avalos and María Rosa Bono and Leonardo Vargas and Valeska Simon and Elias Leiva-Salcedo and Cecilia Vial and Juan Hormazabal and Lina Jimena Cortes and Daniel Valdés and Ana M Sandino and Mónica Imarai and Claudio Acuña-Castillo},
doi = {10.3389/fimmu.2021.766278},
issn = {1664-3224},
year = {2021},
date = {2021-01-01},
journal = {Front Immunol},
volume = {12},
pages = {766278},
abstract = {CoronaVac vaccine from Sinovac Life Science is currently being used in several countries. In Chile, the effectiveness of preventing hospitalization is higher than 80% with a vaccination schedule. However, to date, there are no data about immune response induction or specific memory. For this reason, we recruited 15 volunteers without previous suspected/diagnosed COVID-19 and with negative PCR over time to evaluate the immune response to CoronaVac 28 and 90 days after the second immunization (dpi). The CoronaVac administration induces total and neutralizing anti-spike antibodies in all vaccinated volunteers at 28 and 90 dpi. Furthermore, using ELISpot analysis to assay cellular immune responses against SARS-CoV-2 spike protein, we found an increase in IFN-gamma- and Granzyme B-producing cells in vaccinated volunteers at 28 and 90 dpi. Together, our results indicate that CoronaVac induces a robust humoral immune response and cellular immune memory of at least 90 dpi.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
CoronaVac vaccine from Sinovac Life Science is currently being used in several countries. In Chile, the effectiveness of preventing hospitalization is higher than 80% with a vaccination schedule. However, to date, there are no data about immune response induction or specific memory. For this reason, we recruited 15 volunteers without previous suspected/diagnosed COVID-19 and with negative PCR over time to evaluate the immune response to CoronaVac 28 and 90 days after the second immunization (dpi). The CoronaVac administration induces total and neutralizing anti-spike antibodies in all vaccinated volunteers at 28 and 90 dpi. Furthermore, using ELISpot analysis to assay cellular immune responses against SARS-CoV-2 spike protein, we found an increase in IFN-gamma- and Granzyme B-producing cells in vaccinated volunteers at 28 and 90 dpi. Together, our results indicate that CoronaVac induces a robust humoral immune response and cellular immune memory of at least 90 dpi.
Figueroa, Fabian; Vega-Gibson, Alonso; Catrileo, Joseline; Gaete-Argel, Aracelly; Riquelme-Barrios, Sebastian; Alonso-Palomares, Luis Antonio; Tapia, Lorena I; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo; Acevedo, Monica L
N -Methyladenosine Negatively Regulates Human Respiratory Syncytial Virus Replication Journal Article
In: Front Cell Dev Biol, vol. 9, pp. 739445, 2021, ISSN: 2296-634X.
@article{pmid34671602,
title = {N -Methyladenosine Negatively Regulates Human Respiratory Syncytial Virus Replication},
author = {Fabian Figueroa and Alonso Vega-Gibson and Joseline Catrileo and Aracelly Gaete-Argel and Sebastian Riquelme-Barrios and Luis Antonio Alonso-Palomares and Lorena I Tapia and Fernando Valiente-Echeverría and Ricardo Soto-Rifo and Monica L Acevedo},
doi = {10.3389/fcell.2021.739445},
issn = {2296-634X},
year = {2021},
date = {2021-01-01},
journal = {Front Cell Dev Biol},
volume = {9},
pages = {739445},
abstract = {N-methyladenosine (mA) is the most abundant internal modification described in eukaryotic mRNA and several viral RNA including human respiratory syncytial virus (HRSV). Here, we evaluated the impact of mA writers, erasers and readers on HRSV genomic RNA accumulation and inclusion bodies assembly during viral replication. We observed that the METTL3/METTL14 mA writer complex plays a negative role in HRSV protein synthesis and viral titers, while mA erasers FTO and ALKBH5 had the opposite effect. We also observed that mA readers YTHDF1-3 bind to the viral genomic RNA inducing a decrease in its intracellular levels and thus, inhibiting viral replication. Finally, we observed that overexpression of YTHDFs proteins caused a decrease in the size of inclusion bodies (IBs), accompanied by an increase in their number. METTL3 knockdown cells showed an opposite effect indicating that the dynamics of IBs assembly and coalescence are strongly affected by mA readers in a mechanism dependent on mA writers. Taken together, our results demonstrated that the mA modification negatively affects HRSV replication, possibly through a mechanism involving the assembly of inclusion bodies, the main factories of viral genomic RNA synthesis.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
N-methyladenosine (mA) is the most abundant internal modification described in eukaryotic mRNA and several viral RNA including human respiratory syncytial virus (HRSV). Here, we evaluated the impact of mA writers, erasers and readers on HRSV genomic RNA accumulation and inclusion bodies assembly during viral replication. We observed that the METTL3/METTL14 mA writer complex plays a negative role in HRSV protein synthesis and viral titers, while mA erasers FTO and ALKBH5 had the opposite effect. We also observed that mA readers YTHDF1-3 bind to the viral genomic RNA inducing a decrease in its intracellular levels and thus, inhibiting viral replication. Finally, we observed that overexpression of YTHDFs proteins caused a decrease in the size of inclusion bodies (IBs), accompanied by an increase in their number. METTL3 knockdown cells showed an opposite effect indicating that the dynamics of IBs assembly and coalescence are strongly affected by mA readers in a mechanism dependent on mA writers. Taken together, our results demonstrated that the mA modification negatively affects HRSV replication, possibly through a mechanism involving the assembly of inclusion bodies, the main factories of viral genomic RNA synthesis.
Lopez-Verges, Sandra; Valiente-Echeverría, Fernando; Godoy-Faúndez, Alex; Rivas, David Fernandez; Urbani, Bernardo; Berger, Juan José; Carmona-Mora, Paulina
Call to Action: Supporting Latin American Early Career Researchers on the Quest for Sustainable Development in the Region Journal Article
In: Front Res Metr Anal, vol. 6, pp. 657120, 2021, ISSN: 2504-0537.
@article{pmid34056515,
title = {Call to Action: Supporting Latin American Early Career Researchers on the Quest for Sustainable Development in the Region},
author = {Sandra Lopez-Verges and Fernando Valiente-Echeverría and Alex Godoy-Faúndez and David Fernandez Rivas and Bernardo Urbani and Juan José Berger and Paulina Carmona-Mora},
doi = {10.3389/frma.2021.657120},
issn = {2504-0537},
year = {2021},
date = {2021-01-01},
journal = {Front Res Metr Anal},
volume = {6},
pages = {657120},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Gaete-Argel, Aracelly; Velásquez, Felipe; Márquez, Chantal L; Rojas-Araya, Barbara; Bueno-Nieto, Constanza; Marín-Rojas, Josefina; Cuevas-Zúñiga, Miguel; Soto-Rifo, Ricardo; Valiente-Echeverría, Fernando
Tellurite Promotes Stress Granules and Nuclear SG-Like Assembly in Response to Oxidative Stress and DNA Damage Journal Article
In: Front Cell Dev Biol, vol. 9, pp. 622057, 2021, ISSN: 2296-634X.
@article{pmid33681200,
title = {Tellurite Promotes Stress Granules and Nuclear SG-Like Assembly in Response to Oxidative Stress and DNA Damage},
author = {Aracelly Gaete-Argel and Felipe Velásquez and Chantal L Márquez and Barbara Rojas-Araya and Constanza Bueno-Nieto and Josefina Marín-Rojas and Miguel Cuevas-Zúñiga and Ricardo Soto-Rifo and Fernando Valiente-Echeverría},
doi = {10.3389/fcell.2021.622057},
issn = {2296-634X},
year = {2021},
date = {2021-01-01},
journal = {Front Cell Dev Biol},
volume = {9},
pages = {622057},
abstract = {Tellurium oxyanion, tellurite ( ), is a highly toxic compound for many organisms. Its presence in the environment has increased over the past years due to industrial manufacturing processes and has been associated with adverse effects on human health. Although tellurite induces the phosphorylation of eIF2α, DNA damage and oxidative stress, the molecular mechanisms related to the cellular responses to tellurite-induced stress are poorly understood. In this work, we evaluated the ability of tellurite to induce phosphorylation of eIF2α, stress granules (SGs) assembly and their relationship with DNA damage in U2OS cells. We demonstrate that tellurite promotes the assembly of cytoplasmic SGs. Unexpectedly, tellurite also induces the assembly of nuclear SGs. Interestingly, we observed that the presence of tellurite-induced nuclear SGs correlates with γH2AX foci. However, although HO also induce DNA damage, no nuclear SGs were observed. Our data show that tellurite promotes the assembly of cytoplasmic and nuclear SGs in response to oxidative stress and DNA damage, revealing a new aspect of cellular stress response mediated by the assembly of nuclear stress granules.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Tellurium oxyanion, tellurite ( ), is a highly toxic compound for many organisms. Its presence in the environment has increased over the past years due to industrial manufacturing processes and has been associated with adverse effects on human health. Although tellurite induces the phosphorylation of eIF2α, DNA damage and oxidative stress, the molecular mechanisms related to the cellular responses to tellurite-induced stress are poorly understood. In this work, we evaluated the ability of tellurite to induce phosphorylation of eIF2α, stress granules (SGs) assembly and their relationship with DNA damage in U2OS cells. We demonstrate that tellurite promotes the assembly of cytoplasmic SGs. Unexpectedly, tellurite also induces the assembly of nuclear SGs. Interestingly, we observed that the presence of tellurite-induced nuclear SGs correlates with γH2AX foci. However, although HO also induce DNA damage, no nuclear SGs were observed. Our data show that tellurite promotes the assembly of cytoplasmic and nuclear SGs in response to oxidative stress and DNA damage, revealing a new aspect of cellular stress response mediated by the assembly of nuclear stress granules.
González-Stegmaier, R; Cereceda, K; Briones, J L; Beltran-Pávez, C; Oyarzún-Arrau, A; Riquelme-Barrios, S; Selman, C; Yarad, F; Mahave, M; Caglevic, C; Morales, R; Aguirre, A; Valiente-Echeverría, F; Soto-Rifo, R; Marsiglia, H; Gazitua, R; Villarroel-Espindola, F
Seroconversion and Abundance of IgG Antibodies against S1-RBD of SARS-CoV-2 and Neutralizing Activity in the Chilean Population Journal Article
In: J Immunol Res, vol. 2021, pp. 6680337, 2021, ISSN: 2314-7156.
@article{pmid33644235,
title = {Seroconversion and Abundance of IgG Antibodies against S1-RBD of SARS-CoV-2 and Neutralizing Activity in the Chilean Population},
author = {R González-Stegmaier and K Cereceda and J L Briones and C Beltran-Pávez and A Oyarzún-Arrau and S Riquelme-Barrios and C Selman and F Yarad and M Mahave and C Caglevic and R Morales and A Aguirre and F Valiente-Echeverría and R Soto-Rifo and H Marsiglia and R Gazitua and F Villarroel-Espindola},
doi = {10.1155/2021/6680337},
issn = {2314-7156},
year = {2021},
date = {2021-01-01},
journal = {J Immunol Res},
volume = {2021},
pages = {6680337},
abstract = {COVID-19 is a pandemic caused by SARS-CoV-2. In Chile, half a million people have been infected and more than 16,000 have died from COVID-19. As part of the clinical trial NCT04384588, we quantified IgG against S1-RBD of SARS-CoV-2 (anti-RBD) in recovered people in Santiago and evaluated their suitability as COVID-19 convalescent plasma donors. ELISA and a luminescent SARS-CoV-2 pseudotype were used for IgG and neutralizing antibody quantification. 72.9% of the convalescent population (468 of 639) showed seroconversion (5-55 g/mL anti-RBD IgG) and were suitable candidates for plasma donation. Analysis by gender, age, and days after symptom offset did not show significant differences. Neutralizing activity correlated with an increased concentration of anti-RBD IgG ( < 0.0001) and showed a high variability between donors. We confirmed that the majority of the Chilean patients have developed anti-SARS-CoV-2 antibodies. The quantification of anti-RBD IgG in convalescent plasma donors is necessary to increase the detection of neutralizing antibodies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
COVID-19 is a pandemic caused by SARS-CoV-2. In Chile, half a million people have been infected and more than 16,000 have died from COVID-19. As part of the clinical trial NCT04384588, we quantified IgG against S1-RBD of SARS-CoV-2 (anti-RBD) in recovered people in Santiago and evaluated their suitability as COVID-19 convalescent plasma donors. ELISA and a luminescent SARS-CoV-2 pseudotype were used for IgG and neutralizing antibody quantification. 72.9% of the convalescent population (468 of 639) showed seroconversion (5-55 g/mL anti-RBD IgG) and were suitable candidates for plasma donation. Analysis by gender, age, and days after symptom offset did not show significant differences. Neutralizing activity correlated with an increased concentration of anti-RBD IgG ( < 0.0001) and showed a high variability between donors. We confirmed that the majority of the Chilean patients have developed anti-SARS-CoV-2 antibodies. The quantification of anti-RBD IgG in convalescent plasma donors is necessary to increase the detection of neutralizing antibodies.
Toro-Ascuy, Daniela; Gaete-Argel, Aracelly; Rojas-Celis, Victoria; Valiente-Echeverria, Fernando
In Situ Hybridization-Proximity Ligation Assay (ISH-PLA) to Study the Interaction of HIV-1 RNA and Remodeling Proteins Journal Article
In: Methods Mol Biol, vol. 2209, pp. 307–319, 2021, ISSN: 1940-6029.
@article{pmid33201477,
title = {In Situ Hybridization-Proximity Ligation Assay (ISH-PLA) to Study the Interaction of HIV-1 RNA and Remodeling Proteins},
author = {Daniela Toro-Ascuy and Aracelly Gaete-Argel and Victoria Rojas-Celis and Fernando Valiente-Echeverria},
doi = {10.1007/978-1-0716-0935-4_19},
issn = {1940-6029},
year = {2021},
date = {2021-01-01},
journal = {Methods Mol Biol},
volume = {2209},
pages = {307--319},
abstract = {The mechanisms involved in the posttranscriptional control of the replicative cycle of the human immunodeficiency virus (HIV), specifically the molecular events which allow the interaction between the viral genomic RNA (gRNA) and the cellular machinery for the transport, translation, or intracellular packaging, have not been yet elucidated. In this chapter, we describe the in situ hybridization-proximity ligation assay (ISH-PLA) to characterize interactions between the genomic RNA (gRNA) of HIV-1 and viral proteins or host proteins involved in nuclear export and translation initiation. We also present data that validate the ISH-PLA as a simple and useful tool to study HIV-1 gRNA-protein interactions within cells.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The mechanisms involved in the posttranscriptional control of the replicative cycle of the human immunodeficiency virus (HIV), specifically the molecular events which allow the interaction between the viral genomic RNA (gRNA) and the cellular machinery for the transport, translation, or intracellular packaging, have not been yet elucidated. In this chapter, we describe the in situ hybridization-proximity ligation assay (ISH-PLA) to characterize interactions between the genomic RNA (gRNA) of HIV-1 and viral proteins or host proteins involved in nuclear export and translation initiation. We also present data that validate the ISH-PLA as a simple and useful tool to study HIV-1 gRNA-protein interactions within cells.
Beltrán-Pavez, Carolina; Alonso-Palomares, Luis A; Valiente-Echeverría, Fernando; Gaggero, Aldo; Soto-Rifo, Ricardo; Barriga, Gonzalo P
Accuracy of a RT-qPCR SARS-CoV-2 detection assay without prior RNA extraction Journal Article
In: J Virol Methods, vol. 287, pp. 113969, 2021, ISSN: 1879-0984.
@article{pmid32918932,
title = {Accuracy of a RT-qPCR SARS-CoV-2 detection assay without prior RNA extraction},
author = {Carolina Beltrán-Pavez and Luis A Alonso-Palomares and Fernando Valiente-Echeverría and Aldo Gaggero and Ricardo Soto-Rifo and Gonzalo P Barriga},
doi = {10.1016/j.jviromet.2020.113969},
issn = {1879-0984},
year = {2021},
date = {2021-01-01},
journal = {J Virol Methods},
volume = {287},
pages = {113969},
abstract = {The current COVID-19 pandemic constitutes a threat to the population worldwide with over 21 million infected people. There is an urgent need for the development of rapid and massive detection tools as well as the identification and isolation of infected individuals. we sought to evaluate different RT-qPCR kits and protocols to evaluate the best approach to be used omitting an RNA extraction step. We have investigated the sensitivity and performance of different commercially available RT-qPCR kits in detecting SARS-CoV-2 using 80 extracted RNA and NSS from COVID-19 diagnosed patients. We evaluated the ability of each kit to detect viral RNA from both kit-extracted or directly from a pre-boiled NSS observing that direct RNA detection is possible when Ct values are lower than 30 with the three kits tested. Since SARS-CoV-2 testing in most locations occurs once COVID-19 symptoms are evident and, therefore, viral loads are expected to be high, our protocol will be useful in supporting SARS-CoV-2 diagnosis, especially in America where COVID-19 cases have exploded in the recent weeks as well as in low- and middle-income countries, which would not have massive access to kit-based diagnosis. The information provided in this work paves the way for the development of more efficient SARS-CoV-2 detection approaches avoiding an RNA extraction step.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The current COVID-19 pandemic constitutes a threat to the population worldwide with over 21 million infected people. There is an urgent need for the development of rapid and massive detection tools as well as the identification and isolation of infected individuals. we sought to evaluate different RT-qPCR kits and protocols to evaluate the best approach to be used omitting an RNA extraction step. We have investigated the sensitivity and performance of different commercially available RT-qPCR kits in detecting SARS-CoV-2 using 80 extracted RNA and NSS from COVID-19 diagnosed patients. We evaluated the ability of each kit to detect viral RNA from both kit-extracted or directly from a pre-boiled NSS observing that direct RNA detection is possible when Ct values are lower than 30 with the three kits tested. Since SARS-CoV-2 testing in most locations occurs once COVID-19 symptoms are evident and, therefore, viral loads are expected to be high, our protocol will be useful in supporting SARS-CoV-2 diagnosis, especially in America where COVID-19 cases have exploded in the recent weeks as well as in low- and middle-income countries, which would not have massive access to kit-based diagnosis. The information provided in this work paves the way for the development of more efficient SARS-CoV-2 detection approaches avoiding an RNA extraction step.
2020
Velásquez, Felipe; Marín-Rojas, Josefina; Soto-Rifo, Ricardo; Torres, Alexia; Canto, Felipe Del; Valiente-Echeverría, Fernando
HS and Enterotoxigenic Hinder Stress Granule Assembly Journal Article
In: Microorganisms, vol. 9, no. 1, 2020, ISSN: 2076-2607.
@article{pmid33374562,
title = { HS and Enterotoxigenic Hinder Stress Granule Assembly},
author = {Felipe Velásquez and Josefina Marín-Rojas and Ricardo Soto-Rifo and Alexia Torres and Felipe Del Canto and Fernando Valiente-Echeverría},
doi = {10.3390/microorganisms9010017},
issn = {2076-2607},
year = {2020},
date = {2020-12-01},
journal = {Microorganisms},
volume = {9},
number = {1},
abstract = {, one of the most abundant bacterial species in the human gut microbiota, has developed a mutualistic relationship with its host, regulating immunological responses. In contrast, enterotoxigenic (ETEC), one of the main etiologic agents of diarrheal morbidity and mortality in children under the age of five in developing countries, has developed mechanisms to reduce the immune-activator effect to carry out a successful infection. Following infection, the host cell initiates the shutting-off of protein synthesis and stress granule (SG) assembly. This is mostly mediated by the phosphorylation of translation initiator factor 2α (eIF2α). We therefore evaluated the ability of a non-pathogenic strain ( HS) and an ETEC strain (ETEC 1766a) to induce stress granule assembly, even in response to exogenous stresses. In this work, we found that infection with HS or ETEC 1766a prevents SG assembly in Caco-2 cells treated with sodium arsenite (Ars) after infection. We also show that this effect occurs through an eIF2α phosphorylation (eIF2α-P)-dependent mechanism. Understanding how bacteria counters host stress responses will lay the groundwork for new therapeutic strategies to bolster host cell immune defenses against these pathogens.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
, one of the most abundant bacterial species in the human gut microbiota, has developed a mutualistic relationship with its host, regulating immunological responses. In contrast, enterotoxigenic (ETEC), one of the main etiologic agents of diarrheal morbidity and mortality in children under the age of five in developing countries, has developed mechanisms to reduce the immune-activator effect to carry out a successful infection. Following infection, the host cell initiates the shutting-off of protein synthesis and stress granule (SG) assembly. This is mostly mediated by the phosphorylation of translation initiator factor 2α (eIF2α). We therefore evaluated the ability of a non-pathogenic strain ( HS) and an ETEC strain (ETEC 1766a) to induce stress granule assembly, even in response to exogenous stresses. In this work, we found that infection with HS or ETEC 1766a prevents SG assembly in Caco-2 cells treated with sodium arsenite (Ars) after infection. We also show that this effect occurs through an eIF2α phosphorylation (eIF2α-P)-dependent mechanism. Understanding how bacteria counters host stress responses will lay the groundwork for new therapeutic strategies to bolster host cell immune defenses against these pathogens.
Oyarzún-Arrau, Aarón; Alonso-Palomares, Luis; Valiente-Echeverría, Fernando; Osorio, Fabiola; Soto-Rifo, Ricardo
Crosstalk between RNA Metabolism and Cellular Stress Responses during Zika Virus Replication Journal Article
In: Pathogens, vol. 9, no. 3, 2020, ISSN: 2076-0817.
@article{pmid32106582,
title = {Crosstalk between RNA Metabolism and Cellular Stress Responses during Zika Virus Replication},
author = {Aarón Oyarzún-Arrau and Luis Alonso-Palomares and Fernando Valiente-Echeverría and Fabiola Osorio and Ricardo Soto-Rifo},
doi = {10.3390/pathogens9030158},
issn = {2076-0817},
year = {2020},
date = {2020-02-01},
journal = {Pathogens},
volume = {9},
number = {3},
abstract = {Zika virus (ZIKV) is a mosquito-borne virus associated with neurological disorders such as Guillain-Barré syndrome and microcephaly. In humans, ZIKV is able to replicate in cell types from different tissues including placental cells, neurons, and microglia. This intricate virus-cell interaction is accompanied by virally induced changes in the infected cell aimed to promote viral replication as well as cellular responses aimed to counteract or tolerate the virus. Early in the infection, the 11-kb positive-sense RNA genome recruit ribosomes in the cytoplasm and the complex is translocated to the endoplasmic reticulum (ER) for viral protein synthesis. In this process, ZIKV replication is known to induce cellular stress, which triggers both the expression of innate immune genes and the phosphorylation of eukaryotic translation initiation factor 2 (eIF2α), shutting-off host protein synthesis. Remodeling of the ER during ZIKV replication also triggers the unfolded protein response (UPR), which induces changes in the cellular transcriptional landscapes aimed to tolerate infection or trigger apoptosis. Alternatively, ZIKV replication induces changes in the adenosine methylation patterns of specific host mRNAs, which have different consequences in viral replication and cellular fate. In addition, the ZIKV RNA genome undergoes adenosine methylation by the host machinery, which results in the inhibition of viral replication. However, despite these relevant findings, the full scope of these processes to the outcome of infection remains poorly elucidated. This review summarizes relevant aspects of the complex crosstalk between RNA metabolism and cellular stress responses against ZIKV and discusses their possible impact on viral pathogenesis.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Zika virus (ZIKV) is a mosquito-borne virus associated with neurological disorders such as Guillain-Barré syndrome and microcephaly. In humans, ZIKV is able to replicate in cell types from different tissues including placental cells, neurons, and microglia. This intricate virus-cell interaction is accompanied by virally induced changes in the infected cell aimed to promote viral replication as well as cellular responses aimed to counteract or tolerate the virus. Early in the infection, the 11-kb positive-sense RNA genome recruit ribosomes in the cytoplasm and the complex is translocated to the endoplasmic reticulum (ER) for viral protein synthesis. In this process, ZIKV replication is known to induce cellular stress, which triggers both the expression of innate immune genes and the phosphorylation of eukaryotic translation initiation factor 2 (eIF2α), shutting-off host protein synthesis. Remodeling of the ER during ZIKV replication also triggers the unfolded protein response (UPR), which induces changes in the cellular transcriptional landscapes aimed to tolerate infection or trigger apoptosis. Alternatively, ZIKV replication induces changes in the adenosine methylation patterns of specific host mRNAs, which have different consequences in viral replication and cellular fate. In addition, the ZIKV RNA genome undergoes adenosine methylation by the host machinery, which results in the inhibition of viral replication. However, despite these relevant findings, the full scope of these processes to the outcome of infection remains poorly elucidated. This review summarizes relevant aspects of the complex crosstalk between RNA metabolism and cellular stress responses against ZIKV and discusses their possible impact on viral pathogenesis.
2019
Rojas-Celis, Victoria; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo; Toro-Ascuy, Daniela
New Challenges of HIV-1 Infection: How HIV-1 Attacks and Resides in the Central Nervous System Journal Article
In: Cells, vol. 8, no. 10, 2019, ISSN: 2073-4409.
@article{pmid31614895,
title = {New Challenges of HIV-1 Infection: How HIV-1 Attacks and Resides in the Central Nervous System},
author = {Victoria Rojas-Celis and Fernando Valiente-Echeverría and Ricardo Soto-Rifo and Daniela Toro-Ascuy},
doi = {10.3390/cells8101245},
issn = {2073-4409},
year = {2019},
date = {2019-10-01},
journal = {Cells},
volume = {8},
number = {10},
abstract = {Acquired immunodeficiency syndrome (AIDS) has become one of the most devastating pandemics in recorded history. The main causal agent of AIDS is the human immunodeficiency virus (HIV), which infects various cell types of the immune system that express the CD4 receptor on their surfaces. Today, combined antiretroviral therapy (cART) is the standard treatment for all people with HIV; although it has improved the quality of life of people living with HIV (PLWH), it cannot eliminate the latent reservoir of the virus. Therefore HIV/AIDS has turned from a fatal disease to a chronic disease requiring lifelong treatment. Despite significant viral load suppression, it has been observed that at least half of patients under cART present HIV-associated neurocognitive disorders (HAND), which have been related to HIV-1 infection and replication in the central nervous system (CNS). Several studies have focused on elucidating the mechanism by which HIV-1 can invade the CNS and how it can generate the effects seen in HAND. This review summarizes the research on HIV-1 and its interaction with the CNS with an emphasis on the generation of HAND, how the virus enters the CNS, the relationship between HIV-1 and cells of the CNS, and the effect of cART on these cells.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Acquired immunodeficiency syndrome (AIDS) has become one of the most devastating pandemics in recorded history. The main causal agent of AIDS is the human immunodeficiency virus (HIV), which infects various cell types of the immune system that express the CD4 receptor on their surfaces. Today, combined antiretroviral therapy (cART) is the standard treatment for all people with HIV; although it has improved the quality of life of people living with HIV (PLWH), it cannot eliminate the latent reservoir of the virus. Therefore HIV/AIDS has turned from a fatal disease to a chronic disease requiring lifelong treatment. Despite significant viral load suppression, it has been observed that at least half of patients under cART present HIV-associated neurocognitive disorders (HAND), which have been related to HIV-1 infection and replication in the central nervous system (CNS). Several studies have focused on elucidating the mechanism by which HIV-1 can invade the CNS and how it can generate the effects seen in HAND. This review summarizes the research on HIV-1 and its interaction with the CNS with an emphasis on the generation of HAND, how the virus enters the CNS, the relationship between HIV-1 and cells of the CNS, and the effect of cART on these cells.
Gaete-Argel, Aracelly; Márquez, Chantal L; Barriga, Gonzalo P; Soto-Rifo, Ricardo; Valiente-Echeverría, Fernando
Strategies for Success. Viral Infections and Membraneless Organelles Journal Article
In: Front Cell Infect Microbiol, vol. 9, pp. 336, 2019, ISSN: 2235-2988.
@article{pmid31681621,
title = {Strategies for Success. Viral Infections and Membraneless Organelles},
author = {Aracelly Gaete-Argel and Chantal L Márquez and Gonzalo P Barriga and Ricardo Soto-Rifo and Fernando Valiente-Echeverría},
doi = {10.3389/fcimb.2019.00336},
issn = {2235-2988},
year = {2019},
date = {2019-01-01},
journal = {Front Cell Infect Microbiol},
volume = {9},
pages = {336},
abstract = {Regulation of RNA homeostasis or "RNAstasis" is a central step in eukaryotic gene expression. From transcription to decay, cellular messenger RNAs (mRNAs) associate with specific proteins in order to regulate their entire cycle, including mRNA localization, translation and degradation, among others. The best characterized of such RNA-protein complexes, today named membraneless organelles, are Stress Granules (SGs) and Processing Bodies (PBs) which are involved in RNA storage and RNA decay/storage, respectively. Given that SGs and PBs are generally associated with repression of gene expression, viruses have evolved different mechanisms to counteract their assembly or to use them in their favor to successfully replicate within the host environment. In this review we summarize the current knowledge about the viral regulation of SGs and PBs, which could be a potential novel target for the development of broad-spectrum antiviral therapies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Regulation of RNA homeostasis or "RNAstasis" is a central step in eukaryotic gene expression. From transcription to decay, cellular messenger RNAs (mRNAs) associate with specific proteins in order to regulate their entire cycle, including mRNA localization, translation and degradation, among others. The best characterized of such RNA-protein complexes, today named membraneless organelles, are Stress Granules (SGs) and Processing Bodies (PBs) which are involved in RNA storage and RNA decay/storage, respectively. Given that SGs and PBs are generally associated with repression of gene expression, viruses have evolved different mechanisms to counteract their assembly or to use them in their favor to successfully replicate within the host environment. In this review we summarize the current knowledge about the viral regulation of SGs and PBs, which could be a potential novel target for the development of broad-spectrum antiviral therapies.
2018
Toro-Ascuy, Daniela; Rojas-Araya, Bárbara; García-de-Gracia, Francisco; Rojas-Fuentes, Cecilia; Pereira-Montecinos, Camila; Gaete-Argel, Aracelly; Valiente-Echeverría, Fernando; Ohlmann, Théophile; Soto-Rifo, Ricardo
A Rev-CBP80-eIF4AI complex drives Gag synthesis from the HIV-1 unspliced mRNA Journal Article
In: Nucleic Acids Res, vol. 46, no. 21, pp. 11539–11552, 2018, ISSN: 1362-4962.
@article{pmid30239828,
title = {A Rev-CBP80-eIF4AI complex drives Gag synthesis from the HIV-1 unspliced mRNA},
author = {Daniela Toro-Ascuy and Bárbara Rojas-Araya and Francisco García-de-Gracia and Cecilia Rojas-Fuentes and Camila Pereira-Montecinos and Aracelly Gaete-Argel and Fernando Valiente-Echeverría and Théophile Ohlmann and Ricardo Soto-Rifo},
doi = {10.1093/nar/gky851},
issn = {1362-4962},
year = {2018},
date = {2018-11-01},
journal = {Nucleic Acids Res},
volume = {46},
number = {21},
pages = {11539--11552},
abstract = {Gag synthesis from the full-length unspliced mRNA is critical for the production of the viral progeny during human immunodeficiency virus type-1 (HIV-1) replication. While most spliced mRNAs follow the canonical gene expression pathway in which the recruitment of the nuclear cap-binding complex (CBC) and the exon junction complex (EJC) largely stimulates the rates of nuclear export and translation, the unspliced mRNA relies on the viral protein Rev to reach the cytoplasm and recruit the host translational machinery. Here, we confirm that Rev ensures high levels of Gag synthesis by driving nuclear export and translation of the unspliced mRNA. These functions of Rev are supported by the CBC subunit CBP80, which binds Rev and the unspliced mRNA in the nucleus and the cytoplasm. We also demonstrate that Rev interacts with the DEAD-box RNA helicase eIF4AI, which translocates to the nucleus and cooperates with the viral protein to promote Gag synthesis. Finally, we show that the Rev/RRE axis is important for the assembly of a CBP80-eIF4AI complex onto the unspliced mRNA. Together, our results provide further evidence towards the understanding of the molecular mechanisms by which Rev drives Gag synthesis from the unspliced mRNA during HIV-1 replication.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Gag synthesis from the full-length unspliced mRNA is critical for the production of the viral progeny during human immunodeficiency virus type-1 (HIV-1) replication. While most spliced mRNAs follow the canonical gene expression pathway in which the recruitment of the nuclear cap-binding complex (CBC) and the exon junction complex (EJC) largely stimulates the rates of nuclear export and translation, the unspliced mRNA relies on the viral protein Rev to reach the cytoplasm and recruit the host translational machinery. Here, we confirm that Rev ensures high levels of Gag synthesis by driving nuclear export and translation of the unspliced mRNA. These functions of Rev are supported by the CBC subunit CBP80, which binds Rev and the unspliced mRNA in the nucleus and the cytoplasm. We also demonstrate that Rev interacts with the DEAD-box RNA helicase eIF4AI, which translocates to the nucleus and cooperates with the viral protein to promote Gag synthesis. Finally, we show that the Rev/RRE axis is important for the assembly of a CBP80-eIF4AI complex onto the unspliced mRNA. Together, our results provide further evidence towards the understanding of the molecular mechanisms by which Rev drives Gag synthesis from the unspliced mRNA during HIV-1 replication.
Riquelme-Barrios, Sebastián; Pereira-Montecinos, Camila; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo
Emerging Roles of N-Methyladenosine on HIV-1 RNA Metabolism and Viral Replication Journal Article
In: Front Microbiol, vol. 9, pp. 576, 2018, ISSN: 1664-302X.
@article{pmid29643844,
title = {Emerging Roles of N-Methyladenosine on HIV-1 RNA Metabolism and Viral Replication},
author = {Sebastián Riquelme-Barrios and Camila Pereira-Montecinos and Fernando Valiente-Echeverría and Ricardo Soto-Rifo},
doi = {10.3389/fmicb.2018.00576},
issn = {1664-302X},
year = {2018},
date = {2018-01-01},
journal = {Front Microbiol},
volume = {9},
pages = {576},
abstract = {N-methyladenosine (mA) is the most abundant internal modification present in Eukaryotic mRNA. The functions of this chemical modification are mediated by mA-binding proteins (mA readers) and regulated by methyltransferases (mA writers) and demethylases (mA erasers), which together are proposed to be responsible of a new layer of post-transcriptional control of gene expression. Despite the presence of mA in a retroviral genome was reported more than 40 years ago, the recent development of sequencing-based technologies allowing the mapping of mA in a transcriptome-wide manner made it possible to identify the topology and dynamics of mA during replication of HIV-1 as well as other viruses. As such, three independent groups recently reported the presence of mA along the HIV-1 genomic RNA (gRNA) and described the impact of cellular mA writers, erasers and readers on different steps of viral RNA metabolism and replication. Interestingly, while two groups reported a positive role of mA at different steps of viral gene expression it was also proposed that the presence of mA within the gRNA reduces viral infectivity by inducing the early degradation of the incoming viral genome. This review summarizes the recent advances in this emerging field and discusses the relevance of mA during HIV-1 replication.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
N-methyladenosine (mA) is the most abundant internal modification present in Eukaryotic mRNA. The functions of this chemical modification are mediated by mA-binding proteins (mA readers) and regulated by methyltransferases (mA writers) and demethylases (mA erasers), which together are proposed to be responsible of a new layer of post-transcriptional control of gene expression. Despite the presence of mA in a retroviral genome was reported more than 40 years ago, the recent development of sequencing-based technologies allowing the mapping of mA in a transcriptome-wide manner made it possible to identify the topology and dynamics of mA during replication of HIV-1 as well as other viruses. As such, three independent groups recently reported the presence of mA along the HIV-1 genomic RNA (gRNA) and described the impact of cellular mA writers, erasers and readers on different steps of viral RNA metabolism and replication. Interestingly, while two groups reported a positive role of mA at different steps of viral gene expression it was also proposed that the presence of mA within the gRNA reduces viral infectivity by inducing the early degradation of the incoming viral genome. This review summarizes the recent advances in this emerging field and discusses the relevance of mA during HIV-1 replication.
2017
Cinti, Alessandro; Sage, Valerie Le; Milev, Miroslav P; Valiente-Echeverría, Fernando; Crossie, Christina; Miron, Marie-Joelle; Panté, Nelly; Olivier, Martin; Mouland, Andrew J
HIV-1 enhances mTORC1 activity and repositions lysosomes to the periphery by co-opting Rag GTPases Journal Article
In: Sci Rep, vol. 7, no. 1, pp. 5515, 2017, ISSN: 2045-2322.
@article{pmid28710431,
title = {HIV-1 enhances mTORC1 activity and repositions lysosomes to the periphery by co-opting Rag GTPases},
author = {Alessandro Cinti and Valerie Le Sage and Miroslav P Milev and Fernando Valiente-Echeverría and Christina Crossie and Marie-Joelle Miron and Nelly Panté and Martin Olivier and Andrew J Mouland},
doi = {10.1038/s41598-017-05410-0},
issn = {2045-2322},
year = {2017},
date = {2017-07-01},
journal = {Sci Rep},
volume = {7},
number = {1},
pages = {5515},
abstract = {HIV-1 co-opts several host machinery to generate a permissive environment for viral replication and transmission. In this work we reveal how HIV-1 impacts the host translation and intracellular vesicular trafficking machineries for protein synthesis and to impede the physiological late endosome/lysosome (LEL) trafficking in stressful conditions. First, HIV-1 enhances the activity of the master regulator of protein synthesis, the mammalian target of rapamycin (mTOR). Second, the virus commandeers mTOR-associated late endosome/lysosome (LEL) trafficking and counteracts metabolic and environmental stress-induced intracellular repositioning of LEL. We then show that the small Rag GTPases, RagA and RagB, are required for the HIV-1-mediated LEL repositioning that is likely mediated by interactions between the Rags and the viral proteins, Gag and Vif. siRNA-mediated depletion of RagA and RagB leads to a loss in mTOR association to LEL and to a blockade of viral particle assembly and release at the plasma membrane with a marked concomitant reduction in virus production. These results show that HIV-1 co-opts fundamental mechanisms that regulate LEL motility and positioning and support the notion that LEL positioning is critical for HIV-1 replication.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
HIV-1 co-opts several host machinery to generate a permissive environment for viral replication and transmission. In this work we reveal how HIV-1 impacts the host translation and intracellular vesicular trafficking machineries for protein synthesis and to impede the physiological late endosome/lysosome (LEL) trafficking in stressful conditions. First, HIV-1 enhances the activity of the master regulator of protein synthesis, the mammalian target of rapamycin (mTOR). Second, the virus commandeers mTOR-associated late endosome/lysosome (LEL) trafficking and counteracts metabolic and environmental stress-induced intracellular repositioning of LEL. We then show that the small Rag GTPases, RagA and RagB, are required for the HIV-1-mediated LEL repositioning that is likely mediated by interactions between the Rags and the viral proteins, Gag and Vif. siRNA-mediated depletion of RagA and RagB leads to a loss in mTOR association to LEL and to a blockade of viral particle assembly and release at the plasma membrane with a marked concomitant reduction in virus production. These results show that HIV-1 co-opts fundamental mechanisms that regulate LEL motility and positioning and support the notion that LEL positioning is critical for HIV-1 replication.
Rojas-Mancilla, Edgardo; Oyarce, Alexis; Verdugo, Viviana; Morales-Verdejo, Cesar; Echeverria, Cesar; Velásquez, Felipe; Chnaiderman, Jonas; Valiente-Echeverría, Fernando; Ramirez-Tagle, Rodrigo
The [Mo₆Cl] Cluster is Biologically Secure and Has Anti-Rotavirus Activity In Vitro Journal Article
In: Molecules, vol. 22, no. 7, 2017, ISSN: 1420-3049.
@article{pmid28678175,
title = {The [Mo₆Cl] Cluster is Biologically Secure and Has Anti-Rotavirus Activity In Vitro},
author = {Edgardo Rojas-Mancilla and Alexis Oyarce and Viviana Verdugo and Cesar Morales-Verdejo and Cesar Echeverria and Felipe Velásquez and Jonas Chnaiderman and Fernando Valiente-Echeverría and Rodrigo Ramirez-Tagle},
doi = {10.3390/molecules22071108},
issn = {1420-3049},
year = {2017},
date = {2017-07-01},
journal = {Molecules},
volume = {22},
number = {7},
abstract = {The molybdenum cluster [Mo₆Cl] is a fluorescent component with potential for use in cell labelling and pharmacology. Biological safety and antiviral properties of the cluster are as yet unknown. Here, we show the effect of acute exposition of human cells and red blood cells to the molybdenum cluster and its interaction with proteins and antiviral activity in vitro. We measured cell viability of HepG2 and EA.hy926 cell lines exposed to increasing concentrations of the cluster (0.1 to 250 µM), by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. Hemolysis and morphological alterations of red blood cells, obtained from healthy donors, exposed to the cluster (10 to 200 µM) at 37 °C were analyzed. Furthermore, quenching of tryptophan residues of albumin was performed. Finally, plaque formation by rotavirus SA11 in MA104 cells treated with the cluster (100 to 300 µM) were analyzed. We found that all doses of the cluster showed similar cell viability, hemolysis, and morphology values, compared to control. Quenching of tryptophan residues of albumin suggests a protein-cluster complex formation. Finally, the cluster showed antiviral activity at 300 µM. These results indicate that the cluster [Mo₆Cl] could be intravenously administered in animals at therapeutic doses for further in vivo studies and might be studied as an antiviral agent.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The molybdenum cluster [Mo₆Cl] is a fluorescent component with potential for use in cell labelling and pharmacology. Biological safety and antiviral properties of the cluster are as yet unknown. Here, we show the effect of acute exposition of human cells and red blood cells to the molybdenum cluster and its interaction with proteins and antiviral activity in vitro. We measured cell viability of HepG2 and EA.hy926 cell lines exposed to increasing concentrations of the cluster (0.1 to 250 µM), by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. Hemolysis and morphological alterations of red blood cells, obtained from healthy donors, exposed to the cluster (10 to 200 µM) at 37 °C were analyzed. Furthermore, quenching of tryptophan residues of albumin was performed. Finally, plaque formation by rotavirus SA11 in MA104 cells treated with the cluster (100 to 300 µM) were analyzed. We found that all doses of the cluster showed similar cell viability, hemolysis, and morphology values, compared to control. Quenching of tryptophan residues of albumin suggests a protein-cluster complex formation. Finally, the cluster showed antiviral activity at 300 µM. These results indicate that the cluster [Mo₆Cl] could be intravenously administered in animals at therapeutic doses for further in vivo studies and might be studied as an antiviral agent.
Pereira-Montecinos, Camila; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo
Epitranscriptomic regulation of viral replication Journal Article
In: Biochim Biophys Acta Gene Regul Mech, vol. 1860, no. 4, pp. 460–471, 2017, ISSN: 1874-9399.
@article{pmid28219769,
title = {Epitranscriptomic regulation of viral replication},
author = {Camila Pereira-Montecinos and Fernando Valiente-Echeverría and Ricardo Soto-Rifo},
doi = {10.1016/j.bbagrm.2017.02.002},
issn = {1874-9399},
year = {2017},
date = {2017-04-01},
journal = {Biochim Biophys Acta Gene Regul Mech},
volume = {1860},
number = {4},
pages = {460--471},
abstract = {RNA plays central roles in biology and novel functions and regulation mechanisms are constantly emerging. To accomplish some of their functions within the cell, RNA molecules undergo hundreds of chemical modifications from which N6-methyladenosine (mA), inosine (I), pseudouridine (ψ) and 5-methylcytosine (5mC) have been described in eukaryotic mRNA. Interestingly, the mA modification was shown to be reversible, adding novel layers of regulation of gene expression through what is now recognized as epitranscriptomics. The development of molecular mapping strategies coupled to next generation sequencing allowed the identification of thousand of modified transcripts in different tissues and under different physiological conditions such as viral infections. As intracellular parasites, viruses are confronted to cellular RNA modifying enzymes and, as a consequence, viral RNA can be chemically modified at some stages of the replication cycle. This review focuses on the chemical modifications of viral RNA and the impact that these modifications have on viral gene expression and the output of infection. A special emphasis is given to mA, which was recently shown to play important yet controversial roles in different steps of the HIV-1, HCV and ZIKV replication cycles.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
RNA plays central roles in biology and novel functions and regulation mechanisms are constantly emerging. To accomplish some of their functions within the cell, RNA molecules undergo hundreds of chemical modifications from which N6-methyladenosine (mA), inosine (I), pseudouridine (ψ) and 5-methylcytosine (5mC) have been described in eukaryotic mRNA. Interestingly, the mA modification was shown to be reversible, adding novel layers of regulation of gene expression through what is now recognized as epitranscriptomics. The development of molecular mapping strategies coupled to next generation sequencing allowed the identification of thousand of modified transcripts in different tissues and under different physiological conditions such as viral infections. As intracellular parasites, viruses are confronted to cellular RNA modifying enzymes and, as a consequence, viral RNA can be chemically modified at some stages of the replication cycle. This review focuses on the chemical modifications of viral RNA and the impact that these modifications have on viral gene expression and the output of infection. A special emphasis is given to mA, which was recently shown to play important yet controversial roles in different steps of the HIV-1, HCV and ZIKV replication cycles.
2016
Toro-Ascuy, Daniela; Rojas-Araya, Bárbara; Valiente-Echeverría, Fernando; Soto-Rifo, Ricardo
Interactions between the HIV-1 Unspliced mRNA and Host mRNA Decay Machineries Journal Article
In: Viruses, vol. 8, no. 11, 2016, ISSN: 1999-4915.
@article{pmid27886048,
title = {Interactions between the HIV-1 Unspliced mRNA and Host mRNA Decay Machineries},
author = {Daniela Toro-Ascuy and Bárbara Rojas-Araya and Fernando Valiente-Echeverría and Ricardo Soto-Rifo},
doi = {10.3390/v8110320},
issn = {1999-4915},
year = {2016},
date = {2016-11-01},
journal = {Viruses},
volume = {8},
number = {11},
abstract = {The human immunodeficiency virus type-1 (HIV-1) unspliced transcript is used both as mRNA for the synthesis of structural proteins and as the packaged genome. Given the presence of retained introns and instability AU-rich sequences, this viral transcript is normally retained and degraded in the nucleus of host cells unless the viral protein REV is present. As such, the stability of the HIV-1 unspliced mRNA must be particularly controlled in the nucleus and the cytoplasm in order to ensure proper levels of this viral mRNA for translation and viral particle formation. During its journey, the HIV-1 unspliced mRNA assembles into highly specific messenger ribonucleoproteins (mRNPs) containing many different host proteins, amongst which are well-known regulators of cytoplasmic mRNA decay pathways such as up-frameshift suppressor 1 homolog (UPF1), Staufen double-stranded RNA binding protein 1/2 (STAU1/2), or components of miRNA-induced silencing complex (miRISC) and processing bodies (PBs). More recently, the HIV-1 unspliced mRNA was shown to contain ⁶-methyladenosine (m⁶A), allowing the recruitment of YTH ⁶-methyladenosine RNA binding protein 2 (YTHDF2), an m⁶A reader host protein involved in mRNA decay. Interestingly, these host proteins involved in mRNA decay were shown to play positive roles in viral gene expression and viral particle assembly, suggesting that HIV-1 interacts with mRNA decay components to successfully accomplish viral replication. This review summarizes the state of the art in terms of the interactions between HIV-1 unspliced mRNA and components of different host mRNA decay machineries.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The human immunodeficiency virus type-1 (HIV-1) unspliced transcript is used both as mRNA for the synthesis of structural proteins and as the packaged genome. Given the presence of retained introns and instability AU-rich sequences, this viral transcript is normally retained and degraded in the nucleus of host cells unless the viral protein REV is present. As such, the stability of the HIV-1 unspliced mRNA must be particularly controlled in the nucleus and the cytoplasm in order to ensure proper levels of this viral mRNA for translation and viral particle formation. During its journey, the HIV-1 unspliced mRNA assembles into highly specific messenger ribonucleoproteins (mRNPs) containing many different host proteins, amongst which are well-known regulators of cytoplasmic mRNA decay pathways such as up-frameshift suppressor 1 homolog (UPF1), Staufen double-stranded RNA binding protein 1/2 (STAU1/2), or components of miRNA-induced silencing complex (miRISC) and processing bodies (PBs). More recently, the HIV-1 unspliced mRNA was shown to contain ⁶-methyladenosine (m⁶A), allowing the recruitment of YTH ⁶-methyladenosine RNA binding protein 2 (YTHDF2), an m⁶A reader host protein involved in mRNA decay. Interestingly, these host proteins involved in mRNA decay were shown to play positive roles in viral gene expression and viral particle assembly, suggesting that HIV-1 interacts with mRNA decay components to successfully accomplish viral replication. This review summarizes the state of the art in terms of the interactions between HIV-1 unspliced mRNA and components of different host mRNA decay machineries.
Poblete-Durán, Natalia; Prades-Pérez, Yara; Vera-Otarola, Jorge; Soto-Rifo, Ricardo; Valiente-Echeverría, Fernando
Who Regulates Whom? An Overview of RNA Granules and Viral Infections Journal Article
In: Viruses, vol. 8, no. 7, 2016, ISSN: 1999-4915.
@article{pmid27367717,
title = {Who Regulates Whom? An Overview of RNA Granules and Viral Infections},
author = {Natalia Poblete-Durán and Yara Prades-Pérez and Jorge Vera-Otarola and Ricardo Soto-Rifo and Fernando Valiente-Echeverría},
doi = {10.3390/v8070180},
issn = {1999-4915},
year = {2016},
date = {2016-06-01},
journal = {Viruses},
volume = {8},
number = {7},
abstract = {After viral infection, host cells respond by mounting an anti-viral stress response in order to create a hostile atmosphere for viral replication, leading to the shut-off of mRNA translation (protein synthesis) and the assembly of RNA granules. Two of these RNA granules have been well characterized in yeast and mammalian cells, stress granules (SGs), which are translationally silent sites of RNA triage and processing bodies (PBs), which are involved in mRNA degradation. This review discusses the role of these RNA granules in the evasion of anti-viral stress responses through virus-induced remodeling of cellular ribonucleoproteins (RNPs).},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
After viral infection, host cells respond by mounting an anti-viral stress response in order to create a hostile atmosphere for viral replication, leading to the shut-off of mRNA translation (protein synthesis) and the assembly of RNA granules. Two of these RNA granules have been well characterized in yeast and mammalian cells, stress granules (SGs), which are translationally silent sites of RNA triage and processing bodies (PBs), which are involved in mRNA degradation. This review discusses the role of these RNA granules in the evasion of anti-viral stress responses through virus-induced remodeling of cellular ribonucleoproteins (RNPs).
Fröhlich, Alvaro; Rojas-Araya, Bárbara; Pereira-Montecinos, Camila; Dellarossa, Alessandra; Toro-Ascuy, Daniela; Prades-Pérez, Yara; García-de-Gracia, Francisco; Garcés-Alday, Andrea; Rubilar, Paulina S; Valiente-Echeverría, Fernando; Ohlmann, Théophile; Soto-Rifo, Ricardo
DEAD-box RNA helicase DDX3 connects CRM1-dependent nuclear export and translation of the HIV-1 unspliced mRNA through its N-terminal domain Journal Article
In: Biochim Biophys Acta, vol. 1859, no. 5, pp. 719–730, 2016, ISSN: 0006-3002.
@article{pmid27012366,
title = {DEAD-box RNA helicase DDX3 connects CRM1-dependent nuclear export and translation of the HIV-1 unspliced mRNA through its N-terminal domain},
author = {Alvaro Fröhlich and Bárbara Rojas-Araya and Camila Pereira-Montecinos and Alessandra Dellarossa and Daniela Toro-Ascuy and Yara Prades-Pérez and Francisco García-de-Gracia and Andrea Garcés-Alday and Paulina S Rubilar and Fernando Valiente-Echeverría and Théophile Ohlmann and Ricardo Soto-Rifo},
doi = {10.1016/j.bbagrm.2016.03.009},
issn = {0006-3002},
year = {2016},
date = {2016-05-01},
journal = {Biochim Biophys Acta},
volume = {1859},
number = {5},
pages = {719--730},
abstract = {DEAD-box RNA helicase DDX3 is a host factor essential for HIV-1 replication and thus, a potential target for novel therapies aimed to overcome viral resistance. Previous studies have shown that DDX3 promotes nuclear export and translation of the HIV-1 unspliced mRNA. Although the function of DDX3 during both processes requires its catalytic activity, it is unknown whether other domains surrounding the helicase core are involved. Here, we show the involvement of the N- and C-terminal domains of DDX3 in the regulation of HIV-1 unspliced mRNA translation. Our results suggest that the intrinsically disordered N-terminal domain of DDX3 regulates its functions in translation by acting prior to the recruitment of the 43S pre-initiation complex onto the viral 5'-UTR. Interestingly, this regulation was conserved in HIV-2 and was dependent on the CRM1-dependent nuclear export pathway suggesting a role of the RNA helicase in interconnecting nuclear export with ribosome recruitment of the viral unspliced mRNA. This specific function of DDX3 during HIV gene expression could be exploited as an alternative target for pharmaceutical intervention.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
DEAD-box RNA helicase DDX3 is a host factor essential for HIV-1 replication and thus, a potential target for novel therapies aimed to overcome viral resistance. Previous studies have shown that DDX3 promotes nuclear export and translation of the HIV-1 unspliced mRNA. Although the function of DDX3 during both processes requires its catalytic activity, it is unknown whether other domains surrounding the helicase core are involved. Here, we show the involvement of the N- and C-terminal domains of DDX3 in the regulation of HIV-1 unspliced mRNA translation. Our results suggest that the intrinsically disordered N-terminal domain of DDX3 regulates its functions in translation by acting prior to the recruitment of the 43S pre-initiation complex onto the viral 5'-UTR. Interestingly, this regulation was conserved in HIV-2 and was dependent on the CRM1-dependent nuclear export pathway suggesting a role of the RNA helicase in interconnecting nuclear export with ribosome recruitment of the viral unspliced mRNA. This specific function of DDX3 during HIV gene expression could be exploited as an alternative target for pharmaceutical intervention.
2015
Sage, Valerie Le; Cinti, Alessandro; Valiente-Echeverría, Fernando; Mouland, Andrew J
Proteomic analysis of HIV-1 Gag interacting partners using proximity-dependent biotinylation Journal Article
In: Virol J, vol. 12, pp. 138, 2015, ISSN: 1743-422X.
@article{pmid26362536,
title = {Proteomic analysis of HIV-1 Gag interacting partners using proximity-dependent biotinylation},
author = {Valerie Le Sage and Alessandro Cinti and Fernando Valiente-Echeverría and Andrew J Mouland},
doi = {10.1186/s12985-015-0365-6},
issn = {1743-422X},
year = {2015},
date = {2015-09-01},
journal = {Virol J},
volume = {12},
pages = {138},
abstract = {BACKGROUND: The human immunodeficiency virus type 1 (HIV-1) Gag polyprotein is necessary and sufficient to assemble non-infectious particles. Given that HIV-1 subverts many host proteins at all stages of its life cycle, it is essential to identify these interactions as potential targets for antiretroviral therapy.
FINDINGS: This work demonstrates the use of proximity-dependent biotin identification (BioID) of host proteins and complexes that are proximal to the N-terminal domains of the HIV-1 Gag polyprotein. Two of the hits identified in the BioID screen were validated by immunoprecipation and confirmed the interaction of DDX17 and RPS6 with HIV-1 Gag.
CONCLUSIONS: Our results show that BioID is both a successful and complementary method to screen for nearby interacting proteins of HIV-1 Gag during the replicative cycle in different cell lines.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: The human immunodeficiency virus type 1 (HIV-1) Gag polyprotein is necessary and sufficient to assemble non-infectious particles. Given that HIV-1 subverts many host proteins at all stages of its life cycle, it is essential to identify these interactions as potential targets for antiretroviral therapy.
FINDINGS: This work demonstrates the use of proximity-dependent biotin identification (BioID) of host proteins and complexes that are proximal to the N-terminal domains of the HIV-1 Gag polyprotein. Two of the hits identified in the BioID screen were validated by immunoprecipation and confirmed the interaction of DDX17 and RPS6 with HIV-1 Gag.
CONCLUSIONS: Our results show that BioID is both a successful and complementary method to screen for nearby interacting proteins of HIV-1 Gag during the replicative cycle in different cell lines.
FINDINGS: This work demonstrates the use of proximity-dependent biotin identification (BioID) of host proteins and complexes that are proximal to the N-terminal domains of the HIV-1 Gag polyprotein. Two of the hits identified in the BioID screen were validated by immunoprecipation and confirmed the interaction of DDX17 and RPS6 with HIV-1 Gag.
CONCLUSIONS: Our results show that BioID is both a successful and complementary method to screen for nearby interacting proteins of HIV-1 Gag during the replicative cycle in different cell lines.
Valiente-Echeverría, Fernando; Hermoso, Marcela A; Soto-Rifo, Ricardo
RNA helicase DDX3: at the crossroad of viral replication and antiviral immunity Journal Article
In: Rev Med Virol, vol. 25, no. 5, pp. 286–299, 2015, ISSN: 1099-1654.
@article{pmid26174373,
title = {RNA helicase DDX3: at the crossroad of viral replication and antiviral immunity},
author = {Fernando Valiente-Echeverría and Marcela A Hermoso and Ricardo Soto-Rifo},
doi = {10.1002/rmv.1845},
issn = {1099-1654},
year = {2015},
date = {2015-09-01},
journal = {Rev Med Virol},
volume = {25},
number = {5},
pages = {286--299},
abstract = {Asp-Glu-Ala-Asp (DEAD)-box polypeptide 3, or DDX3, belongs to the DEAD-box family of ATP-dependent RNA helicases and is known to play different roles in RNA metabolism ranging from transcription to nuclear export, translation, and assembly of stress granules. In addition, there is growing evidence that DDX3 is a component of the innate immune response against viral infections. As such, DDX3 has been shown to play roles both upstream and downstream of I-kappa beta kinase ε (IKKε)/TANK-binding kinase 1, leading to IFN-β production. Interestingly, several RNA viruses, including human threats such as HIV-1 and hepatitis C virus, hijack DDX3 to accomplish various steps of their replication cycles. Thus, it seems that viruses have evolved to exploit DDX3's functions while threatening the innate immune response. Understanding this interesting dichotomy in DDX3 function will help us not only to improve our knowledge of virus-host interactions but also to develop novel antiviral drugs targeting the multifaceted roles of DDX3 in viral replication.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Asp-Glu-Ala-Asp (DEAD)-box polypeptide 3, or DDX3, belongs to the DEAD-box family of ATP-dependent RNA helicases and is known to play different roles in RNA metabolism ranging from transcription to nuclear export, translation, and assembly of stress granules. In addition, there is growing evidence that DDX3 is a component of the innate immune response against viral infections. As such, DDX3 has been shown to play roles both upstream and downstream of I-kappa beta kinase ε (IKKε)/TANK-binding kinase 1, leading to IFN-β production. Interestingly, several RNA viruses, including human threats such as HIV-1 and hepatitis C virus, hijack DDX3 to accomplish various steps of their replication cycles. Thus, it seems that viruses have evolved to exploit DDX3's functions while threatening the innate immune response. Understanding this interesting dichotomy in DDX3 function will help us not only to improve our knowledge of virus-host interactions but also to develop novel antiviral drugs targeting the multifaceted roles of DDX3 in viral replication.
2014
Soto-Rifo, Ricardo; Valiente-Echeverria, Fernando; Rubilar, Paulina S; Garcia-de-Gracia, Francisco; Ricci, Emiliano P; Limousin, Taran; Décimo, Didier; Mouland, Andrew J; Ohlmann, Théophile
HIV-2 genomic RNA accumulates in stress granules in the absence of active translation Journal Article
In: Nucleic Acids Res, vol. 42, no. 20, pp. 12861–12875, 2014, ISSN: 1362-4962.
@article{pmid25352557,
title = {HIV-2 genomic RNA accumulates in stress granules in the absence of active translation},
author = {Ricardo Soto-Rifo and Fernando Valiente-Echeverria and Paulina S Rubilar and Francisco Garcia-de-Gracia and Emiliano P Ricci and Taran Limousin and Didier Décimo and Andrew J Mouland and Théophile Ohlmann},
doi = {10.1093/nar/gku1017},
issn = {1362-4962},
year = {2014},
date = {2014-11-01},
journal = {Nucleic Acids Res},
volume = {42},
number = {20},
pages = {12861--12875},
abstract = {During the post-transcriptional events of the HIV-2 replication cycle, the full-length unspliced genomic RNA (gRNA) is first used as an mRNA to synthesize Gag and Gag-Pol proteins and then packaged into progeny virions. However, the mechanisms responsible for the coordinate usage of the gRNA during these two mutually exclusive events are poorly understood. Here, we present evidence showing that HIV-2 expression induces stress granule assembly in cultured cells. This contrasts with HIV-1, which interferes with stress granules assembly even upon induced cellular stress. Moreover, we observed that the RNA-binding protein and stress granules assembly factor TIAR associates with the gRNA to form a TIAR-HIV-2 ribonucleoprotein (TH2RNP) complex localizing diffuse in the cytoplasm or aggregated in stress granules. Although the assembly of TH2RNP in stress granules did not require the binding of the Gag protein to the gRNA, we observed that increased levels of Gag promoted both translational arrest and stress granule assembly. Moreover, HIV-2 Gag also localizes to stress granules in the absence of a 'packageable' gRNA. Our results indicate that the HIV-2 gRNA is compartmentalized in stress granules in the absence of active translation prior to being selected for packaging by the Gag polyprotein.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
During the post-transcriptional events of the HIV-2 replication cycle, the full-length unspliced genomic RNA (gRNA) is first used as an mRNA to synthesize Gag and Gag-Pol proteins and then packaged into progeny virions. However, the mechanisms responsible for the coordinate usage of the gRNA during these two mutually exclusive events are poorly understood. Here, we present evidence showing that HIV-2 expression induces stress granule assembly in cultured cells. This contrasts with HIV-1, which interferes with stress granules assembly even upon induced cellular stress. Moreover, we observed that the RNA-binding protein and stress granules assembly factor TIAR associates with the gRNA to form a TIAR-HIV-2 ribonucleoprotein (TH2RNP) complex localizing diffuse in the cytoplasm or aggregated in stress granules. Although the assembly of TH2RNP in stress granules did not require the binding of the Gag protein to the gRNA, we observed that increased levels of Gag promoted both translational arrest and stress granule assembly. Moreover, HIV-2 Gag also localizes to stress granules in the absence of a 'packageable' gRNA. Our results indicate that the HIV-2 gRNA is compartmentalized in stress granules in the absence of active translation prior to being selected for packaging by the Gag polyprotein.
Sage, Valerie Le; Mouland, Andrew J; Valiente-Echeverría, Fernando
Roles of HIV-1 capsid in viral replication and immune evasion Journal Article
In: Virus Res, vol. 193, pp. 116–129, 2014, ISSN: 1872-7492.
@article{pmid25036886,
title = {Roles of HIV-1 capsid in viral replication and immune evasion},
author = {Valerie Le Sage and Andrew J Mouland and Fernando Valiente-Echeverría},
doi = {10.1016/j.virusres.2014.07.010},
issn = {1872-7492},
year = {2014},
date = {2014-11-01},
journal = {Virus Res},
volume = {193},
pages = {116--129},
abstract = {The primary roles of the human immunodeficiency virus type 1 (HIV-1) capsid (CA) protein are to encapsidate and protect the viral RNA genome. It is becoming increasing apparent that HIV-1 CA is a multifunctional protein that acts early during infection to coordinate uncoating, reverse transcription, nuclear import of the pre-integration complex and integration of double stranded viral DNA into the host genome. Additionally, numerous recent studies indicate that CA is playing a crucial function in HIV-1 immune evasion. Here we summarize the current knowledge on HIV-1 CA and its interactions with the host cell to promote infection. The fact that CA engages in a number of different protein-protein interactions with the host makes it an interesting target for the development of new potent antiviral agents.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The primary roles of the human immunodeficiency virus type 1 (HIV-1) capsid (CA) protein are to encapsidate and protect the viral RNA genome. It is becoming increasing apparent that HIV-1 CA is a multifunctional protein that acts early during infection to coordinate uncoating, reverse transcription, nuclear import of the pre-integration complex and integration of double stranded viral DNA into the host genome. Additionally, numerous recent studies indicate that CA is playing a crucial function in HIV-1 immune evasion. Here we summarize the current knowledge on HIV-1 CA and its interactions with the host cell to promote infection. The fact that CA engages in a number of different protein-protein interactions with the host makes it an interesting target for the development of new potent antiviral agents.
Valiente-Echeverría, Fernando; Melnychuk, Luca; Vyboh, Kishanda; Ajamian, Lara; Gallouzi, Imed-Eddine; Bernard, Nicole; Mouland, Andrew J
eEF2 and Ras-GAP SH3 domain-binding protein (G3BP1) modulate stress granule assembly during HIV-1 infection Journal Article
In: Nat Commun, vol. 5, pp. 4819, 2014, ISSN: 2041-1723.
@article{pmid25229650,
title = {eEF2 and Ras-GAP SH3 domain-binding protein (G3BP1) modulate stress granule assembly during HIV-1 infection},
author = {Fernando Valiente-Echeverría and Luca Melnychuk and Kishanda Vyboh and Lara Ajamian and Imed-Eddine Gallouzi and Nicole Bernard and Andrew J Mouland},
doi = {10.1038/ncomms5819},
issn = {2041-1723},
year = {2014},
date = {2014-09-01},
journal = {Nat Commun},
volume = {5},
pages = {4819},
abstract = {Stress granules (SG) are translationally silent sites of RNA triage induced by environmental stresses including viral infection. Here we show that HIV-1 Gag blocks SG assembly irrespective of eIF2α phosphorylation and even when SG assembly is forced by overexpression of Ras-GAP SH3 domain-binding protein (G3BP1) or TIAR. The overexposed loops in the amino-terminal capsid domain of Gag and host eukaryotic elongation factor 2 (eEF2) are found to be critical for the SG blockade via interaction. Moreover, cyclophilin A (CypA) stabilizes the Gag-eEF2 association. eEF2 depletion not only lifts the SG blockade but also results in impaired virus production and infectivity. Gag also disassembles preformed SGs by recruiting G3BP1, thereby displacing eEF2, revealing another unsuspected virus-host interaction involved in the HIV-1-imposed SG blockade. Understanding how HIV-1 counters anti-viral stress responses will lay the groundwork for new therapeutic strategies to bolster host cell immune defences against HIV-1 and other pathogens.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Stress granules (SG) are translationally silent sites of RNA triage induced by environmental stresses including viral infection. Here we show that HIV-1 Gag blocks SG assembly irrespective of eIF2α phosphorylation and even when SG assembly is forced by overexpression of Ras-GAP SH3 domain-binding protein (G3BP1) or TIAR. The overexposed loops in the amino-terminal capsid domain of Gag and host eukaryotic elongation factor 2 (eEF2) are found to be critical for the SG blockade via interaction. Moreover, cyclophilin A (CypA) stabilizes the Gag-eEF2 association. eEF2 depletion not only lifts the SG blockade but also results in impaired virus production and infectivity. Gag also disassembles preformed SGs by recruiting G3BP1, thereby displacing eEF2, revealing another unsuspected virus-host interaction involved in the HIV-1-imposed SG blockade. Understanding how HIV-1 counters anti-viral stress responses will lay the groundwork for new therapeutic strategies to bolster host cell immune defences against HIV-1 and other pathogens.
2013
Gordon, Heather; Ajamian, Lara; Valiente-Echeverrìa, Fernando; Lévesque, Kathy; Rigby, William F; Mouland, Andrew J
Depletion of hnRNP A2/B1 overrides the nuclear retention of the HIV-1 genomic RNA Journal Article
In: RNA Biol, vol. 10, no. 11, pp. 1714–1725, 2013, ISSN: 1555-8584.
@article{pmid24157614,
title = {Depletion of hnRNP A2/B1 overrides the nuclear retention of the HIV-1 genomic RNA},
author = {Heather Gordon and Lara Ajamian and Fernando Valiente-Echeverrìa and Kathy Lévesque and William F Rigby and Andrew J Mouland},
doi = {10.4161/rna.26542},
issn = {1555-8584},
year = {2013},
date = {2013-11-01},
journal = {RNA Biol},
volume = {10},
number = {11},
pages = {1714--1725},
abstract = {hnRNP A2 is a cellular protein that is important for nucleocytoplasmic and cytosolic trafficking of the HIV-1 genomic RNA. Both hnRNP A2's interaction with HIV-1 RNA and its expression levels influence the activities of Rev in mediating nucleocytoplasmic export of the HIV-1 genomic RNA. While the lack of Rev expression during HIV-1 gene expression results in nuclear retention of HIV-1 genomic RNA, we show here by fluorescence in situ hybridization and fractionation studies that the genomic RNA translocates to the cytoplasm when hnRNP A2/B1 are depleted from cells. Polyribosome analyses revealed that the genomic RNA was shunted into a cytoplasmic, dense polyribosomal fraction. This fraction contained several RNA-binding proteins involved in viral gene expression and RNA trafficking but did not contain the translation initiation factor, eIF4G1. Amino acid incorporation into nascent polypeptides in this fraction was also greatly reduced, demonstrating that this fraction contains mRNAs that are poorly translated. These results demonstrate that hnRNP A2/B1 expression plays roles in the nuclear retention of the HIV-1 genomic RNA in the absence of Rev and in the release of the genomic RNA from translationally inactive, cytoplasmic RNP complexes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
hnRNP A2 is a cellular protein that is important for nucleocytoplasmic and cytosolic trafficking of the HIV-1 genomic RNA. Both hnRNP A2's interaction with HIV-1 RNA and its expression levels influence the activities of Rev in mediating nucleocytoplasmic export of the HIV-1 genomic RNA. While the lack of Rev expression during HIV-1 gene expression results in nuclear retention of HIV-1 genomic RNA, we show here by fluorescence in situ hybridization and fractionation studies that the genomic RNA translocates to the cytoplasm when hnRNP A2/B1 are depleted from cells. Polyribosome analyses revealed that the genomic RNA was shunted into a cytoplasmic, dense polyribosomal fraction. This fraction contained several RNA-binding proteins involved in viral gene expression and RNA trafficking but did not contain the translation initiation factor, eIF4G1. Amino acid incorporation into nascent polypeptides in this fraction was also greatly reduced, demonstrating that this fraction contains mRNAs that are poorly translated. These results demonstrate that hnRNP A2/B1 expression plays roles in the nuclear retention of the HIV-1 genomic RNA in the absence of Rev and in the release of the genomic RNA from translationally inactive, cytoplasmic RNP complexes.