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Characterizing the Relationship Between Neutralization Sensitivity and env Gene Diversity During ART Suppression
Although antiretroviral therapy (ART) successfully suppresses HIV-1 replication, ART-treated individuals must maintain therapy to avoid rebound from an integrated viral reservoir. Strategies to limit or clear this reservoir are urgently needed. Individuals infected for longer periods prior to ART ap...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8479156/ https://www.ncbi.nlm.nih.gov/pubmed/34603284 http://dx.doi.org/10.3389/fimmu.2021.710327 |
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author | Wilson, Andrew Shakhtour, Leyn Ward, Adam Ren, Yanqin Recarey, Melina Stevenson, Eva Korom, Maria Kovacs, Colin Benko, Erika Jones, R. Brad Lynch, Rebecca M. |
author_facet | Wilson, Andrew Shakhtour, Leyn Ward, Adam Ren, Yanqin Recarey, Melina Stevenson, Eva Korom, Maria Kovacs, Colin Benko, Erika Jones, R. Brad Lynch, Rebecca M. |
author_sort | Wilson, Andrew |
collection | PubMed |
description | Although antiretroviral therapy (ART) successfully suppresses HIV-1 replication, ART-treated individuals must maintain therapy to avoid rebound from an integrated viral reservoir. Strategies to limit or clear this reservoir are urgently needed. Individuals infected for longer periods prior to ART appear to harbor more genetically diverse virus, but the roles of duration of infection and viral diversity in the humoral immune response remain to be studied. We aim to clarify a role, if any, for autologous and heterologous antibodies in multi-pronged approaches to clearing infection. To that end, we have characterized the breadths and potencies of antibody responses in individuals with varying durations of infection and HIV-1 envelope (env) gene diversity as well as the sensitivity of their inducible virus reservoir to broadly neutralizing antibodies (bNAbs). Plasma was collected from 8 well-characterized HIV-1(+) males on ART with varied durations of active infection. HIV envs from reservoir-derived outgrowth viruses were amplified and single genome sequenced in order to measure genetic diversity in each participant. IgG from plasma was analyzed for binding titers against gp41 and gp120 proteins, and for neutralizing titers against a global HIV-1 reference panel as well as autologous outgrowth viruses. The sensitivity to bNAbs of these same autologous viruses was measured. Overall, we observed that greater env diversity was associated with higher neutralizing titers against the global panel and also increased resistance to certain bNAbs. Despite the presence of robust anti-HIV-1 antibody titers, we did not observe potent neutralization against autologous viruses. In fact, 3 of 8 participants harbored viruses that were completely resistant to the highest tested concentration of autologous IgG. That this lack of neutralization was observed regardless of ART duration or viral diversity suggests that the inducible reservoir harbors ‘escaped’ viruses (that co-evolved with autologous antibody responses), rather than proviruses archived from earlier in infection. Finally, we observed that viruses resistant to autologous neutralization remained sensitive to bNAbs, especially CD4bs and MPER bNAbs. Overall, our data suggest that the inducible reservoir is relatively resistant to autologous antibodies and that individuals with limited virus variation in the env gene, such as those who start ART early in infection, are more likely to be sensitive to bNAb treatment. |
format | Online Article Text |
id | pubmed-8479156 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-84791562021-09-30 Characterizing the Relationship Between Neutralization Sensitivity and env Gene Diversity During ART Suppression Wilson, Andrew Shakhtour, Leyn Ward, Adam Ren, Yanqin Recarey, Melina Stevenson, Eva Korom, Maria Kovacs, Colin Benko, Erika Jones, R. Brad Lynch, Rebecca M. Front Immunol Immunology Although antiretroviral therapy (ART) successfully suppresses HIV-1 replication, ART-treated individuals must maintain therapy to avoid rebound from an integrated viral reservoir. Strategies to limit or clear this reservoir are urgently needed. Individuals infected for longer periods prior to ART appear to harbor more genetically diverse virus, but the roles of duration of infection and viral diversity in the humoral immune response remain to be studied. We aim to clarify a role, if any, for autologous and heterologous antibodies in multi-pronged approaches to clearing infection. To that end, we have characterized the breadths and potencies of antibody responses in individuals with varying durations of infection and HIV-1 envelope (env) gene diversity as well as the sensitivity of their inducible virus reservoir to broadly neutralizing antibodies (bNAbs). Plasma was collected from 8 well-characterized HIV-1(+) males on ART with varied durations of active infection. HIV envs from reservoir-derived outgrowth viruses were amplified and single genome sequenced in order to measure genetic diversity in each participant. IgG from plasma was analyzed for binding titers against gp41 and gp120 proteins, and for neutralizing titers against a global HIV-1 reference panel as well as autologous outgrowth viruses. The sensitivity to bNAbs of these same autologous viruses was measured. Overall, we observed that greater env diversity was associated with higher neutralizing titers against the global panel and also increased resistance to certain bNAbs. Despite the presence of robust anti-HIV-1 antibody titers, we did not observe potent neutralization against autologous viruses. In fact, 3 of 8 participants harbored viruses that were completely resistant to the highest tested concentration of autologous IgG. That this lack of neutralization was observed regardless of ART duration or viral diversity suggests that the inducible reservoir harbors ‘escaped’ viruses (that co-evolved with autologous antibody responses), rather than proviruses archived from earlier in infection. Finally, we observed that viruses resistant to autologous neutralization remained sensitive to bNAbs, especially CD4bs and MPER bNAbs. Overall, our data suggest that the inducible reservoir is relatively resistant to autologous antibodies and that individuals with limited virus variation in the env gene, such as those who start ART early in infection, are more likely to be sensitive to bNAb treatment. Frontiers Media S.A. 2021-09-15 /pmc/articles/PMC8479156/ /pubmed/34603284 http://dx.doi.org/10.3389/fimmu.2021.710327 Text en Copyright © 2021 Wilson, Shakhtour, Ward, Ren, Recarey, Stevenson, Korom, Kovacs, Benko, Jones and Lynch https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Wilson, Andrew Shakhtour, Leyn Ward, Adam Ren, Yanqin Recarey, Melina Stevenson, Eva Korom, Maria Kovacs, Colin Benko, Erika Jones, R. Brad Lynch, Rebecca M. Characterizing the Relationship Between Neutralization Sensitivity and env Gene Diversity During ART Suppression |
title | Characterizing the Relationship Between Neutralization Sensitivity and env Gene Diversity During ART Suppression |
title_full | Characterizing the Relationship Between Neutralization Sensitivity and env Gene Diversity During ART Suppression |
title_fullStr | Characterizing the Relationship Between Neutralization Sensitivity and env Gene Diversity During ART Suppression |
title_full_unstemmed | Characterizing the Relationship Between Neutralization Sensitivity and env Gene Diversity During ART Suppression |
title_short | Characterizing the Relationship Between Neutralization Sensitivity and env Gene Diversity During ART Suppression |
title_sort | characterizing the relationship between neutralization sensitivity and env gene diversity during art suppression |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8479156/ https://www.ncbi.nlm.nih.gov/pubmed/34603284 http://dx.doi.org/10.3389/fimmu.2021.710327 |
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