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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Viral Escape from Neutralizing Antibodies in Early Subtype A HIV-1 Infection Drives an Increase in Autologous Neutralization Breadth
PLoS Pathogens, Volume 9, No. 2, Article e1003173, Year 2013
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Description
Antibodies that neutralize (nAbs) genetically diverse HIV-1 strains have been recovered from a subset of HIV-1 infected subjects during chronic infection. Exact mechanisms that expand the otherwise narrow neutralization capacity observed during early infection are, however, currently undefined. Here we characterized the earliest nAb responses in a subtype A HIV-1 infected Rwandan seroconverter who later developed moderate cross-clade nAb breadth, using (i) envelope (Env) glycoproteins from the transmitted/founder virus and twenty longitudinal nAb escape variants, (ii) longitudinal autologous plasma, and (iii) autologous monoclonal antibodies (mAbs). Initially, nAbs targeted a single region of gp120, which flanked the V3 domain and involved the alpha2 helix. A single amino acid change at one of three positions in this region conferred early escape. One immunoglobulin heavy chain and two light chains recovered from autologous B cells comprised two mAbs, 19.3H-L1 and 19.3H-L3, which neutralized the founder Env along with one or three of the early escape variants carrying these mutations, respectively. Neither mAb neutralized later nAb escape or heterologous Envs. Crystal structures of the antigen-binding fragments (Fabs) revealed flat epitope contact surfaces, where minimal light chain mutation in 19.3H-L3 allowed for additional antigenic interactions. Resistance to mAb neutralization arose in later Envs through alteration of two glycans spatially adjacent to the initial escape signatures. The cross-neutralizing nAbs that ultimately developed failed to target any of the defined V3-proximal changes generated during the first year of infection in this subject. Our data demonstrate that this subject's first recognized nAb epitope elicited strain-specific mAbs, which incrementally acquired autologous breadth, and directed later B cell responses to target distinct portions of Env. This immune re-focusing could have triggered the evolution of cross-clade antibodies and suggests that exposure to a specific sequence of immune escape variants might promote broad humoral responses during HIV-1 infection. © 2013 Murphy et al.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3585129/bin/ppat.1003173.s001.tif
https://efashare.b-cdn.net/share/pmc/articles/PMC3585129/bin/ppat.1003173.s002.tif
https://efashare.b-cdn.net/share/pmc/articles/PMC3585129/bin/ppat.1003173.s003.docx
Authors & Co-Authors
Murphy, Megan K.
United States, Atlanta
Emory University
Yue, Ling
United States, Atlanta
Emory University
Pan, Ruimin
United States, New York
Nyu Grossman School of Medicine
Boliar, Saikat
United States, Atlanta
Emory University
Sethi, Anurag
United States, Los Alamos
Los Alamos National Laboratory
Tian, Jianhui
United States, Los Alamos
Los Alamos National Laboratory
Pfafferot, Katja
United Kingdom, Oxford
Nuffield Department of Medicine
Karita, Etienne
Rwanda, Kigali
Projet San Francisco
Allen, Susan A.
United States, Atlanta
Emory University
Cormier, Emmanuel G.
United States, New York
International Aids Vaccine Initiative
Goepfert, Paul A.
United States, Birmingham
The University of Alabama at Birmingham
Borrow, Persephone
United Kingdom, Oxford
Nuffield Department of Medicine
Robinson, James E.
United States, New Orleans
Tulane University School of Medicine
Gnanakaran, Sandrasegaram
United States, Los Alamos
Los Alamos National Laboratory
Hunter, Eric
United States, Atlanta
Emory University
Kong, Xiangpeng
United States, New York
Nyu Grossman School of Medicine
Derdeyn, Cynthia A.
United States, Atlanta
Emory University
Statistics
Citations: 54
Authors: 17
Affiliations: 8
Identifiers
Doi:
10.1371/journal.ppat.1003173
ISSN:
15537366
e-ISSN:
15537374
Research Areas
Cancer
Infectious Diseases
Study Design
Cohort Study