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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
4E10-resistant HIV-1 isolated from four subjects with rare membrane-proximal external region polymorphisms
PLoS ONE, Volume 5, No. 3, Article e9786, Year 2010
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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. © 2010 Nakamura et al.
Authors & Co-Authors
Nakamura, Kyle J.
United States, Los Angeles
Children's Hospital Los Angeles
United States, Los Angeles
Keck School of Medicine of Usc
Gach, Johannes Simon
United States, San Diego
Scripps Research Institute
Jones, Laura
United States, Los Angeles
Children's Hospital Los Angeles
Semrau, Katherine E.A.
United States, Boston
School of Public Health
Walter, Jan
United States, Los Angeles
Children's Hospital Los Angeles
Bibollet-Ruche, Frédéric
United States, Birmingham
The University of Alabama at Birmingham
Decker, Julie M.
United States, Birmingham
The University of Alabama at Birmingham
Heath, Laura M.
United States, Seattle
University of Washington
Decker, William Don
United States, Los Angeles
Children's Hospital Los Angeles
Sinkala, Moses M.
Zambia, Lusaka
Lusaka District Health Management Team
Kankasa, Chipepo
Zambia, Lusaka
University Teaching Hospital Lusaka
Thea, Donald M.
United States, Boston
School of Public Health
Mullins, James I.
United States, Seattle
University of Washington
Kuhn, Louise
United States, New York
Columbia University
Zwick, Michael B.
United States, San Diego
Scripps Research Institute
Aldrovandi, Grace M.
United States, Los Angeles
Children's Hospital Los Angeles
Statistics
Citations: 23
Authors: 16
Affiliations: 9
Identifiers
Doi:
10.1371/journal.pone.0009786
e-ISSN:
19326203
Research Areas
Infectious Diseases
Maternal And Child Health