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Nat Commun. 2015 Sep 25;6:8167. doi: 10.1038/ncomms9167.

Antibodies to a conformational epitope on gp41 neutralize HIV-1 by destabilizing the Env spike.

Author information

1
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
2
International AIDS Vaccine Initiative Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla California 92037, USA.
3
Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
4
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
5
Department of Medicinal Microbiology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.
6
Weill Medical College of Cornell University, New York, New York 10065, USA.
7
Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA.
8
Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts 02114, USA.
9
Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USA.
10
Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.

Abstract

The recent identification of three broadly neutralizing antibodies (bnAbs) against gp120-gp41 interface epitopes has expanded the targetable surface on the HIV-1 envelope glycoprotein (Env) trimer. By using biochemical, biophysical and computational methods, we map the previously unknown trimer epitopes of two related antibodies, 3BC315 and 3BC176. A cryo-EM reconstruction of a soluble Env trimer bound to 3BC315 Fab at 9.3 Å resolution reveals that the antibody binds between two gp41 protomers, and neutralizes the virus by accelerating trimer decay. In contrast, bnAb 35O22 binding to a partially overlapping quaternary epitope at the gp120-gp41 interface does not induce decay. A conserved gp41-proximal glycan at N88 was also shown to play a role in the binding kinetics of 3BC176 and 3BC315. Finally, our data suggest that the dynamic structure of the Env trimer influences exposure of bnAb epitopes.

PMID:
26404402
PMCID:
PMC4586043
DOI:
10.1038/ncomms9167
[Indexed for MEDLINE]
Free PMC Article

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