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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2013
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.
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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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