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PLoS Pathog. 2015 Oct 30;11(10):e1005238. doi: 10.1371/journal.ppat.1005238. eCollection 2015 Oct.

A New Glycan-Dependent CD4-Binding Site Neutralizing Antibody Exerts Pressure on HIV-1 In Vivo.

Author information

1
Laboratory of Molecular Immunology, The Rockefeller University, New York, New York, United States of America.
2
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, United States of America.
3
Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.
4
Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
5
Department of Microbiology and Immunology, Weill Medical College, Cornell University, New York, New York, United States of America.
6
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
7
Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America; Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America.
8
First Department of Internal Medicine, University Hospital of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany.
9
Laboratory of Molecular Immunology, The Rockefeller University, New York, New York, United States of America; Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America.

Abstract

The CD4 binding site (CD4bs) on the envelope glycoprotein is a major site of vulnerability that is conserved among different HIV-1 isolates. Many broadly neutralizing antibodies (bNAbs) to the CD4bs belong to the VRC01 class, sharing highly restricted origins, recognition mechanisms and viral escape pathways. We sought to isolate new anti-CD4bs bNAbs with different origins and mechanisms of action. Using a gp120 2CC core as bait, we isolated antibodies encoded by IGVH3-21 and IGVL3-1 genes with long CDRH3s that depend on the presence of the N-linked glycan at position-276 for activity. This binding mode is similar to the previously identified antibody HJ16, however the new antibodies identified herein are more potent and broad. The most potent variant, 179NC75, had a geometric mean IC80 value of 0.42 μg/ml against 120 Tier-2 HIV-1 pseudoviruses in the TZM.bl assay. Although this group of CD4bs glycan-dependent antibodies can be broadly and potently neutralizing in vitro, their in vivo activity has not been tested to date. Here, we report that 179NC75 is highly active when administered to HIV-1-infected humanized mice, where it selects for escape variants that lack a glycan site at position-276. The same glycan was absent from the virus isolated from the 179NC75 donor, implying that the antibody also exerts selection pressure in humans.

PMID:
26516768
PMCID:
PMC4627763
DOI:
10.1371/journal.ppat.1005238
[Indexed for MEDLINE]
Free PMC Article

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