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

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 epit...

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Bibliographic Details
Published in:Nature communications 2015-09, Vol.6 (1), p.8167-8167, Article 8167
Main Authors: Lee, Jeong Hyun, Leaman, Daniel P, Kim, Arthur S, Torrents de la Peña, Alba, Sliepen, Kwinten, Yasmeen, Anila, Derking, Ronald, Ramos, Alejandra, de Taeye, Steven W, Ozorowski, Gabriel, Klein, Florian, Burton, Dennis R, Nussenzweig, Michel C, Poignard, Pascal, Moore, John P, Klasse, Per Johan, Sanders, Rogier W, Zwick, Michael B, Wilson, Ian A, Ward, Andrew B
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
Antibodies
Antibodies, Neutralizing
Antibodies, Neutralizing - immunology
Biochemistry, Molecular Biology
Computer Simulation
Cryoelectron Microscopy
Crystallography, X-Ray
Epitope Mapping
Epitopes
HEK293 Cells
HIV Antibodies
HIV Antibodies - immunology
HIV Envelope Protein gp120
HIV Envelope Protein gp120 - immunology
HIV Envelope Protein gp41
HIV Envelope Protein gp41 - immunology
HIV-1
HIV-1 - immunology
Humans
Immunoglobulin Fab Fragments
Immunoglobulin Fab Fragments - immunology
Immunoglobulin G
Immunoglobulin G - immunology
Life Sciences
Models, Molecular
Molecular biophysics
Protein Conformation
Structural Biology
X-ray crystallography
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Summary: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.
ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms9167