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4E10-Resistant HIV-1 Isolated from Four Subjects with Rare Membrane-Proximal External Region Polymorphisms
Human antibody 4E10 targets the highly conserved membrane-proximal external region (MPER) of the HIV-1 transmembrane glycoprotein, gp41, and has extraordinarily broad neutralizing activity. It is considered by many to be a prototype for vaccine development. In this study, we describe four subjects i...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2843716/ https://www.ncbi.nlm.nih.gov/pubmed/20352106 http://dx.doi.org/10.1371/journal.pone.0009786 |
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author | Nakamura, Kyle J. Gach, Johannes S. Jones, Laura Semrau, Katherine Walter, Jan Bibollet-Ruche, Frederic Decker, Julie M. Heath, Laura Decker, William D. Sinkala, Moses Kankasa, Chipepo Thea, Donald Mullins, James Kuhn, Louise Zwick, Michael B. Aldrovandi, Grace M. |
author_facet | Nakamura, Kyle J. Gach, Johannes S. Jones, Laura Semrau, Katherine Walter, Jan Bibollet-Ruche, Frederic Decker, Julie M. Heath, Laura Decker, William D. Sinkala, Moses Kankasa, Chipepo Thea, Donald Mullins, James Kuhn, Louise Zwick, Michael B. Aldrovandi, Grace M. |
author_sort | Nakamura, Kyle J. |
collection | PubMed |
description | Human antibody 4E10 targets the highly conserved membrane-proximal external region (MPER) of the HIV-1 transmembrane glycoprotein, gp41, and has extraordinarily broad neutralizing activity. It is considered by many to be a prototype for vaccine development. In this study, we describe four subjects infected with viruses carrying rare MPER polymorphisms associated with resistance to 4E10 neutralization. In one case resistant virus carrying a W680G substitution was transmitted from mother to infant. We used site-directed mutagenesis to demonstrate that the W680G substitution is necessary for conferring the 4E10-resistant phenotype, but that it is not sufficient to transfer the phenotype to a 4E10-sensitive Env. Our third subject carried Envs with a W680R substitution causing variable resistance to 4E10, indicating that residues outside the MPER are required to confer the phenotype. A fourth subject possessed a F673L substitution previously associated with 4E10 resistance. For all three subjects with W680 polymorphisms, we observed additional residues in the MPER that co-varied with position 680 and preserved charged distributions across this region. Our data provide important caveats for vaccine development targeting the MPER. Naturally occurring Env variants described in our study also represent unique tools for probing the structure-function of HIV-1 envelope. |
format | Text |
id | pubmed-2843716 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-28437162010-03-27 4E10-Resistant HIV-1 Isolated from Four Subjects with Rare Membrane-Proximal External Region Polymorphisms Nakamura, Kyle J. Gach, Johannes S. Jones, Laura Semrau, Katherine Walter, Jan Bibollet-Ruche, Frederic Decker, Julie M. Heath, Laura Decker, William D. Sinkala, Moses Kankasa, Chipepo Thea, Donald Mullins, James Kuhn, Louise Zwick, Michael B. Aldrovandi, Grace M. PLoS One Research Article Human antibody 4E10 targets the highly conserved membrane-proximal external region (MPER) of the HIV-1 transmembrane glycoprotein, gp41, and has extraordinarily broad neutralizing activity. It is considered by many to be a prototype for vaccine development. In this study, we describe four subjects infected with viruses carrying rare MPER polymorphisms associated with resistance to 4E10 neutralization. In one case resistant virus carrying a W680G substitution was transmitted from mother to infant. We used site-directed mutagenesis to demonstrate that the W680G substitution is necessary for conferring the 4E10-resistant phenotype, but that it is not sufficient to transfer the phenotype to a 4E10-sensitive Env. Our third subject carried Envs with a W680R substitution causing variable resistance to 4E10, indicating that residues outside the MPER are required to confer the phenotype. A fourth subject possessed a F673L substitution previously associated with 4E10 resistance. For all three subjects with W680 polymorphisms, we observed additional residues in the MPER that co-varied with position 680 and preserved charged distributions across this region. Our data provide important caveats for vaccine development targeting the MPER. Naturally occurring Env variants described in our study also represent unique tools for probing the structure-function of HIV-1 envelope. Public Library of Science 2010-03-23 /pmc/articles/PMC2843716/ /pubmed/20352106 http://dx.doi.org/10.1371/journal.pone.0009786 Text en Nakamura et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Nakamura, Kyle J. Gach, Johannes S. Jones, Laura Semrau, Katherine Walter, Jan Bibollet-Ruche, Frederic Decker, Julie M. Heath, Laura Decker, William D. Sinkala, Moses Kankasa, Chipepo Thea, Donald Mullins, James Kuhn, Louise Zwick, Michael B. Aldrovandi, Grace M. 4E10-Resistant HIV-1 Isolated from Four Subjects with Rare Membrane-Proximal External Region Polymorphisms |
title | 4E10-Resistant HIV-1 Isolated from Four Subjects with Rare Membrane-Proximal External Region Polymorphisms |
title_full | 4E10-Resistant HIV-1 Isolated from Four Subjects with Rare Membrane-Proximal External Region Polymorphisms |
title_fullStr | 4E10-Resistant HIV-1 Isolated from Four Subjects with Rare Membrane-Proximal External Region Polymorphisms |
title_full_unstemmed | 4E10-Resistant HIV-1 Isolated from Four Subjects with Rare Membrane-Proximal External Region Polymorphisms |
title_short | 4E10-Resistant HIV-1 Isolated from Four Subjects with Rare Membrane-Proximal External Region Polymorphisms |
title_sort | 4e10-resistant hiv-1 isolated from four subjects with rare membrane-proximal external region polymorphisms |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2843716/ https://www.ncbi.nlm.nih.gov/pubmed/20352106 http://dx.doi.org/10.1371/journal.pone.0009786 |
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