Asymmetric recognition of HIV-1 Envelope trimer by V1V2 loop-targeting antibodies

Abstract
Data availability
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Abstract

The HIV-1 envelope (Env) glycoprotein binds to host cell receptors to mediate membrane fusion. The prefusion Env trimer is stabilized by V1V2 loops that interact at the trimer apex. Broadly neutralizing antibodies (bNAbs) against V1V2 loops, exemplified by PG9, bind asymmetrically as a single Fab to the apex of the symmetric Env trimer using a protruding CDRH3 to penetrate the Env glycan shield. Here we characterized a distinct mode of V1V2 epitope recognition by the new bNAb BG1 in which two Fabs bind asymmetrically per Env trimer using a compact CDRH3. Comparisons between cryo-EM structures of Env trimer complexed with BG1 (6.2Å resolution) and PG9 (11.5Å resolution) revealed a new V1V2-targeting strategy by BG1. Analyses of the EM structures provided information relevant to vaccine design including molecular details for different modes of asymmetric recognition of Env trimer and a binding model for BG1 recognition of V1V2 involving glycan flexibility.

Data availability

The following data sets were generated

(2017) BG1-Env-8ANC195 complex
Publicly available at the EMBL_EBI Protein Dtat Bank in Europe (accession no: EMD-8693).

https://www.ebi.ac.uk/pdbe/emdb/8693
(2017) PG9-Env-8ANC195 complex
Publicly available at the EMBL_EBI Protein Dtat Bank in Europe (accession no: EMDB-8695).

https://www.ebi.ac.uk/pdbe/emdb/8695
(2017) BG1 Fab coordinate
Publicly available at the RCSB Protein Data Bank (accession no: 5VVF).

http://www.rcsb.org/pdb/explore/explore.do?structureId=5VVF
(2017) BG1-Env-8ANC195 complex coordinates
Publicly available at the RCSB Protein Data Bank (accession no: 5VIY).

http://www.rcsb.org/pdb/explore/explore.do?structureId=5VIY
(2017) PG9-Env-8ANC195 complex coordinates
Publicly available at the RCSB Protein Data Bank (accession no: 5VJ6).

http://www.rcsb.org/pdb/explore/explore.do?structureId=5VJ6

Article and author information

Author details

Haoqing Wang

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States

Competing interests
No competing interests declared.
Harry B Gristick

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States

Competing interests
No competing interests declared.
Louise Scharf

Therapeutics, 23andMe, Mountain View, United States

Competing interests
No competing interests declared.
Anthony P West

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States

Competing interests
No competing interests declared.
Rachel P Galimidi

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States

Competing interests
No competing interests declared.
Michael S Seaman

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, United States

Competing interests
No competing interests declared.
Natalia T Freund

Department of Clinical Microbiology and Immunology, Tel Aviv University, Tel Aviv, Israel

Competing interests
No competing interests declared.
Michel C Nussenzweig

Laboratory of Molecular Immunology, The Rockefeller University, New York, United States

Competing interests
Michel C Nussenzweig, Senior editor, eLife.
Pamela J Bjorkman

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States

For correspondence
bjorkman@caltech.edu

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-2277-3990

Funding

National Institutes of Health (GM082545-06)

Pamela J Bjorkman

National Institute of Allergy and Infectious Diseases (HIVRAD P01 AI100148)

Michel C Nussenzweig
Pamela J Bjorkman

Bill and Melinda Gates Foundation (1040753)

Michel C Nussenzweig
Pamela J Bjorkman

Comprehensive Antibody-Vaccine Immune Monitoring Consortium (1032144)

Michael S Seaman

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.