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Autoreactivity and broad neutralization of antibodies against HIV-1 are governed by distinct mutations: Implications for vaccine design strategies
Many of the best HIV-1 broadly neutralizing antibodies (bnAbs) known have poly-/autoreactive features that disfavor normal B cell development and maturation, posing a major hurdle in developing an effective HIV-1 vaccine. Key to resolving this problem is to understand if, and to what extent, neutral...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9720396/ https://www.ncbi.nlm.nih.gov/pubmed/36479128 http://dx.doi.org/10.3389/fimmu.2022.977630 |
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author | Li, Xiaojun Liao, Dongmei Li, Zhengyang Li, Jixi Diaz, Marilyn Verkoczy, Laurent Gao, Feng |
author_facet | Li, Xiaojun Liao, Dongmei Li, Zhengyang Li, Jixi Diaz, Marilyn Verkoczy, Laurent Gao, Feng |
author_sort | Li, Xiaojun |
collection | PubMed |
description | Many of the best HIV-1 broadly neutralizing antibodies (bnAbs) known have poly-/autoreactive features that disfavor normal B cell development and maturation, posing a major hurdle in developing an effective HIV-1 vaccine. Key to resolving this problem is to understand if, and to what extent, neutralization breadth-conferring mutations acquired by bnAbs contribute to their autoreactivity. Here, we back-mutated all known changes made by a prototype CD4 binding site-directed bnAb lineage, CH103-106, during its later maturation steps. Strikingly, of 29 mutations examined, only four were crucial for increased autoreactivity, with minimal or no impact on neutralization. Furthermore, three of these residues were clustered in the heavy chain complementarity-determining region 2 (HCDR2). Our results demonstrate that broad neutralization activity and autoreactivity in the CH103-106 bnAb lineage can be governed by a few, distinct mutations during maturation. This provides strong rationale for developing immunogens that favor bnAb lineages bearing “neutralization-only” mutations into current HIV-1 vaccine designs. |
format | Online Article Text |
id | pubmed-9720396 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-97203962022-12-06 Autoreactivity and broad neutralization of antibodies against HIV-1 are governed by distinct mutations: Implications for vaccine design strategies Li, Xiaojun Liao, Dongmei Li, Zhengyang Li, Jixi Diaz, Marilyn Verkoczy, Laurent Gao, Feng Front Immunol Immunology Many of the best HIV-1 broadly neutralizing antibodies (bnAbs) known have poly-/autoreactive features that disfavor normal B cell development and maturation, posing a major hurdle in developing an effective HIV-1 vaccine. Key to resolving this problem is to understand if, and to what extent, neutralization breadth-conferring mutations acquired by bnAbs contribute to their autoreactivity. Here, we back-mutated all known changes made by a prototype CD4 binding site-directed bnAb lineage, CH103-106, during its later maturation steps. Strikingly, of 29 mutations examined, only four were crucial for increased autoreactivity, with minimal or no impact on neutralization. Furthermore, three of these residues were clustered in the heavy chain complementarity-determining region 2 (HCDR2). Our results demonstrate that broad neutralization activity and autoreactivity in the CH103-106 bnAb lineage can be governed by a few, distinct mutations during maturation. This provides strong rationale for developing immunogens that favor bnAb lineages bearing “neutralization-only” mutations into current HIV-1 vaccine designs. Frontiers Media S.A. 2022-11-18 /pmc/articles/PMC9720396/ /pubmed/36479128 http://dx.doi.org/10.3389/fimmu.2022.977630 Text en Copyright © 2022 Li, Liao, Li, Li, Diaz, Verkoczy and Gao 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 Li, Xiaojun Liao, Dongmei Li, Zhengyang Li, Jixi Diaz, Marilyn Verkoczy, Laurent Gao, Feng Autoreactivity and broad neutralization of antibodies against HIV-1 are governed by distinct mutations: Implications for vaccine design strategies |
title | Autoreactivity and broad neutralization of antibodies against HIV-1 are governed by distinct mutations: Implications for vaccine design strategies |
title_full | Autoreactivity and broad neutralization of antibodies against HIV-1 are governed by distinct mutations: Implications for vaccine design strategies |
title_fullStr | Autoreactivity and broad neutralization of antibodies against HIV-1 are governed by distinct mutations: Implications for vaccine design strategies |
title_full_unstemmed | Autoreactivity and broad neutralization of antibodies against HIV-1 are governed by distinct mutations: Implications for vaccine design strategies |
title_short | Autoreactivity and broad neutralization of antibodies against HIV-1 are governed by distinct mutations: Implications for vaccine design strategies |
title_sort | autoreactivity and broad neutralization of antibodies against hiv-1 are governed by distinct mutations: implications for vaccine design strategies |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9720396/ https://www.ncbi.nlm.nih.gov/pubmed/36479128 http://dx.doi.org/10.3389/fimmu.2022.977630 |
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