1. Structural Biology and Molecular Biophysics
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Asymmetric recognition of HIV-1 Envelope trimer by V1V2 loop-targeting antibodies

  1. Haoqing Wang
  2. Harry B Gristick
  3. Louise Scharf
  4. Anthony P West
  5. Rachel P Galimidi
  6. Michael S Seaman
  7. Natalia T Freund
  8. Michel C Nussenzweig
  9. Pamela J Bjorkman  Is a corresponding author
  1. California Institute of Technology, United States
  2. 23andMe, United States
  3. Beth Israel Deaconess Medical Center, United States
  4. Tel Aviv University, Israel
  5. The Rockefeller University, United States
Research Article
  • Cited 25
  • Views 1,706
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Cite this article as: eLife 2017;6:e27389 doi: 10.7554/eLife.27389

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
    1. Haoqing Wang
    2. Harry Gristick
    3. Pamela Bjorkman
    (2017) BG1-Env-8ANC195 complex
    Publicly available at the EMBL_EBI Protein Dtat Bank in Europe (accession no: EMD-8693).
    1. Haoqing Wang
    2. Harry Gristick
    3. Pamela Bjorkm
    (2017) PG9-Env-8ANC195 complex
    Publicly available at the EMBL_EBI Protein Dtat Bank in Europe (accession no: EMDB-8695).
    1. Louise Scharf
    2. Harry Gristick
    3. Pamela Bjorkman
    (2017) BG1 Fab coordinate
    Publicly available at the RCSB Protein Data Bank (accession no: 5VVF).

Article and author information

Author details

  1. Haoqing Wang

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    No competing interests declared.
  2. Harry B Gristick

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    No competing interests declared.
  3. Louise Scharf

    Therapeutics, 23andMe, Mountain View, United States
    Competing interests
    No competing interests declared.
  4. Anthony P West

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    No competing interests declared.
  5. Rachel P Galimidi

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    No competing interests declared.
  6. Michael S Seaman

    Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, United States
    Competing interests
    No competing interests declared.
  7. Natalia T Freund

    Department of Clinical Microbiology and Immunology, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    No competing interests declared.
  8. Michel C Nussenzweig

    Laboratory of Molecular Immunology, The Rockefeller University, New York, United States
    Competing interests
    Michel C Nussenzweig, Senior editor, eLife.
  9. 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.
    ORCID icon "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.

Reviewing Editor

  1. Arup K. Chakraborty, Massachusetts Institute of Technology, United States

Publication history

  1. Received: April 1, 2017
  2. Accepted: May 24, 2017
  3. Accepted Manuscript published: May 26, 2017 (version 1)
  4. Version of Record published: June 15, 2017 (version 2)

Copyright

© 2017, Wang et al.

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.

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