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

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

Version 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.

Metrics

  • 2,084
    Page views
  • 445
    Downloads
  • 37
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
(2017)
Asymmetric recognition of HIV-1 Envelope trimer by V1V2 loop-targeting antibodies
eLife 6:e27389.
https://doi.org/10.7554/eLife.27389

Share this article

https://doi.org/10.7554/eLife.27389

Further reading

    1. Structural Biology and Molecular Biophysics
    Ekaterina Smirnova, Emmanuelle Bignon ... Adam Ben Shem
    Research Article

    Sirtuin 6 (SIRT6) is an NAD+-dependent histone H3 deacetylase that is prominently found associated with chromatin, attenuates transcriptionally active promoters and regulates DNA repair, metabolic homeostasis and lifespan. Unlike other sirtuins, it has low affinity to free histone tails but demonstrates strong binding to nucleosomes. It is poorly understood how SIRT6 docking on nucleosomes stimulates its histone deacetylation activity. Here, we present the structure of human SIRT6 bound to a nucleosome determined by cryogenic electron microscopy. The zinc finger domain of SIRT6 associates tightly with the acidic patch of the nucleosome through multiple arginine anchors. The Rossmann fold domain binds to the terminus of the looser DNA half of the nucleosome, detaching two turns of the DNA from the histone octamer and placing the NAD+ binding pocket close to the DNA exit site. This domain shows flexibility with respect to the fixed zinc finger and moves with, but also relative to, the unwrapped DNA terminus. We apply molecular dynamics simulations of the histone tails in the nucleosome to show that in this mode of interaction, the active site of SIRT6 is perfectly poised to catalyze deacetylation of the H3 histone tail and that the partial unwrapping of the DNA allows even lysines close to the H3 core to reach the enzyme.

    1. Structural Biology and Molecular Biophysics
    Bernhard Schuster
    Insight

    The surface layer of Sulfolobus acidocaldarius consists of a flexible but stable outer protein layer that interacts with an inner, membrane-bound protein.