title: Antibodies to a conformational epitope on gp41 neutralize HIV-1 by destabilizing the Env spike.
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.
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA.|International AIDS Vaccine Initiative Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla California 92037, USA.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Jeong Hyun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Leaman
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Kim
authors.affiliation: Department of Medicinal Microbiology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Alba
authors.initials: A
authors.lastname: Torrents de la Peña
authors.affiliation: Department of Medicinal Microbiology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Kwinten
authors.initials: K
authors.lastname: Sliepen
authors.affiliation: Weill Medical College of Cornell University, New York, New York 10065, USA.
authors.forename: Anila
authors.initials: A
authors.lastname: Yasmeen
authors.affiliation: Department of Medicinal Microbiology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: Derking
authors.affiliation: International AIDS Vaccine Initiative Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla California 92037, USA.|Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Ramos
authors.affiliation: Department of Medicinal Microbiology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Steven W
authors.initials: SW
authors.lastname: de Taeye
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA.|International AIDS Vaccine Initiative Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla California 92037, USA.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Ozorowski
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Klein
authors.affiliation: International AIDS Vaccine Initiative Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla California 92037, USA.|Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.|Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts 02114, USA.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA.|Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
authors.affiliation: International AIDS Vaccine Initiative Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla California 92037, USA.|Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Pascal
authors.initials: P
authors.lastname: Poignard
authors.affiliation: Weill Medical College of Cornell University, New York, New York 10065, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
authors.affiliation: Weill Medical College of Cornell University, New York, New York 10065, USA.
authors.forename: Per Johan
authors.initials: PJ
authors.lastname: Klasse
authors.affiliation: Department of Medicinal Microbiology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.|Weill Medical College of Cornell University, New York, New York 10065, USA.
authors.forename: Rogier W
authors.initials: RW
authors.lastname: Sanders
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Zwick
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA.|International AIDS Vaccine Initiative Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla California 92037, USA.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.|Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA.|International AIDS Vaccine Initiative Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla California 92037, USA.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Ward
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology*; D003198:Computer Simulation; D020285:Cryoelectron Microscopy; D018360:Crystallography, X-Ray; D018604:Epitope Mapping; D000939:Epitopes; D057809:HEK293 Cells; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D008958:Models, Molecular; D011487:Protein Conformation
chemical_list: D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G