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Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies
Broadly neutralizing antibodies (bnAbs) against HIV are believed to be a critical component of the protective responses elicited by an effective HIV vaccine. Neutralizing antibodies against the evolutionarily conserved CD4-binding site (CD4-BS) on the HIV envelope glycoprotein (Env) are capable of i...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3620356/ https://www.ncbi.nlm.nih.gov/pubmed/23530120 http://dx.doi.org/10.1084/jem.20122824 |
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author | McGuire, Andrew T. Hoot, Sam Dreyer, Anita M. Lippy, Adriana Stuart, Andrew Cohen, Kristen W. Jardine, Joseph Menis, Sergey Scheid, Johannes F. West, Anthony P. Schief, William R. Stamatatos, Leonidas |
author_facet | McGuire, Andrew T. Hoot, Sam Dreyer, Anita M. Lippy, Adriana Stuart, Andrew Cohen, Kristen W. Jardine, Joseph Menis, Sergey Scheid, Johannes F. West, Anthony P. Schief, William R. Stamatatos, Leonidas |
author_sort | McGuire, Andrew T. |
collection | PubMed |
description | Broadly neutralizing antibodies (bnAbs) against HIV are believed to be a critical component of the protective responses elicited by an effective HIV vaccine. Neutralizing antibodies against the evolutionarily conserved CD4-binding site (CD4-BS) on the HIV envelope glycoprotein (Env) are capable of inhibiting infection of diverse HIV strains, and have been isolated from HIV-infected individuals. Despite the presence of anti–CD4-BS broadly neutralizing antibody (bnAb) epitopes on recombinant Env, Env immunization has so far failed to elicit such antibodies. Here, we show that Env immunogens fail to engage the germline-reverted forms of known bnAbs that target the CD4-BS. However, we found that the elimination of a conserved glycosylation site located in Loop D and two glycosylation sites located in variable region 5 of Env allows Env-binding to, and activation of, B cells expressing the germline-reverted BCRs of two potent broadly neutralizing antibodies, VRC01 and NIH45-46. Our results offer a possible explanation as to why Env immunogens have been ineffective in stimulating the production of such bNAbs. Importantly, they provide key information as to how such immunogens can be engineered to initiate the process of antibody-affinity maturation against one of the most conserved Env regions. |
format | Online Article Text |
id | pubmed-3620356 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-36203562013-10-08 Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies McGuire, Andrew T. Hoot, Sam Dreyer, Anita M. Lippy, Adriana Stuart, Andrew Cohen, Kristen W. Jardine, Joseph Menis, Sergey Scheid, Johannes F. West, Anthony P. Schief, William R. Stamatatos, Leonidas J Exp Med Brief Definitive Report Broadly neutralizing antibodies (bnAbs) against HIV are believed to be a critical component of the protective responses elicited by an effective HIV vaccine. Neutralizing antibodies against the evolutionarily conserved CD4-binding site (CD4-BS) on the HIV envelope glycoprotein (Env) are capable of inhibiting infection of diverse HIV strains, and have been isolated from HIV-infected individuals. Despite the presence of anti–CD4-BS broadly neutralizing antibody (bnAb) epitopes on recombinant Env, Env immunization has so far failed to elicit such antibodies. Here, we show that Env immunogens fail to engage the germline-reverted forms of known bnAbs that target the CD4-BS. However, we found that the elimination of a conserved glycosylation site located in Loop D and two glycosylation sites located in variable region 5 of Env allows Env-binding to, and activation of, B cells expressing the germline-reverted BCRs of two potent broadly neutralizing antibodies, VRC01 and NIH45-46. Our results offer a possible explanation as to why Env immunogens have been ineffective in stimulating the production of such bNAbs. Importantly, they provide key information as to how such immunogens can be engineered to initiate the process of antibody-affinity maturation against one of the most conserved Env regions. The Rockefeller University Press 2013-04-08 /pmc/articles/PMC3620356/ /pubmed/23530120 http://dx.doi.org/10.1084/jem.20122824 Text en © 2013 McGuire et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Brief Definitive Report McGuire, Andrew T. Hoot, Sam Dreyer, Anita M. Lippy, Adriana Stuart, Andrew Cohen, Kristen W. Jardine, Joseph Menis, Sergey Scheid, Johannes F. West, Anthony P. Schief, William R. Stamatatos, Leonidas Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies |
title | Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies |
title_full | Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies |
title_fullStr | Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies |
title_full_unstemmed | Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies |
title_short | Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies |
title_sort | engineering hiv envelope protein to activate germline b cell receptors of broadly neutralizing anti-cd4 binding site antibodies |
topic | Brief Definitive Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3620356/ https://www.ncbi.nlm.nih.gov/pubmed/23530120 http://dx.doi.org/10.1084/jem.20122824 |
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