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

Jeong Hyun Lee, Daniel P. Leaman, Arthur S. Kim, Alba Torrents de la Peña, Kwinten Sliepen, Anila Yasmeen, Ronald Derking, Alejandra Ramos, Steven W. de Taeye, Gabriel Ozorowski, Florian Klein, Dennis R. Burton, Michel C. Nussenzweig, Pascal Poignard, John P. Moore, Per Johan Klasse, Rogier W. Sanders, Michael B. Zwick, Ian A. Wilson and Andrew B. Ward ()
Additional contact information
Jeong Hyun Lee: The Scripps Research Institute
Daniel P. Leaman: The Scripps Research Institute
Arthur S. Kim: The Scripps Research Institute
Alba Torrents de la Peña: Academic Medical Center
Kwinten Sliepen: Academic Medical Center
Anila Yasmeen: Weill Medical College of Cornell University
Ronald Derking: Academic Medical Center
Alejandra Ramos: International AIDS Vaccine Initiative Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute
Steven W. de Taeye: Academic Medical Center
Gabriel Ozorowski: The Scripps Research Institute
Florian Klein: Laboratory of Molecular Immunology, The Rockefeller University
Dennis R. Burton: International AIDS Vaccine Initiative Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute
Michel C. Nussenzweig: Laboratory of Molecular Immunology, The Rockefeller University
Pascal Poignard: International AIDS Vaccine Initiative Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute
John P. Moore: Weill Medical College of Cornell University
Per Johan Klasse: Weill Medical College of Cornell University
Rogier W. Sanders: Academic Medical Center
Michael B. Zwick: The Scripps Research Institute
Ian A. Wilson: The Scripps Research Institute
Andrew B. Ward: The Scripps Research Institute

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9167

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