Germline VRC01 antibody recognition of a modified clade C HIV-1 envelope trimer and a glycosylated HIV-1 gp120 core

  1. Andrew J Borst
  2. Connor E Weidle
  3. Matthew D Gray
  4. Brandon Frenz
  5. Joost Snijder
  6. M Gordon Joyce
  7. Ivelin S Georgiev
  8. Guillaume BE Stewart-Jones
  9. Peter D Kwong
  10. Andrew T McGuire
  11. Frank DiMaio
  12. Leonidas Stamatatos  Is a corresponding author
  13. Marie Pancera  Is a corresponding author
  14. David Veesler  Is a corresponding author
  1. University of Washington, United States
  2. Fred Hutchinson Cancer Research Center, United States
  3. National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States

Abstract

VRC01 broadly neutralizing antibodies (bnAbs) target the CD4-binding site (CD4BS) of the human immunodeficiency virus-1 (HIV-1) envelope glycoprotein (Env). Unlike mature antibodies, corresponding VRC01 germline precursors poorly bind to Env. Immunogen design has mostly relied on glycan removal from trimeric Env constructs and has had limited success in eliciting mature VRC01 bnAbs. To better understand elicitation of such bnAbs, we characterized the inferred germline precursor of VRC01 in complex with a modified trimeric 426c Env by cryo-electron microscopy and a 426c gp120 core by X-ray crystallography, biolayer interferometry, immunoprecipitation, and glycoproteomics. Our results show VRC01 germline antibodies interacted with a wild-type 426c core lacking variable loops 1-3 in the presence or absence of a glycan at position Asn276, with the latter form binding with higher affinity than the former. Interactions in the presence of an Asn276 oligosaccharide could be enhanced upon carbohydrate shortening, which should be considered for immunogen design.

Data availability

Mass spectrometry data have been deposited to the PRIDE archive under accession number PXD011494. CryoEM maps are available for download from the EMDB under accession numbers EMD-9294 (426cDS-SOSIP D3†-VRC01GL, 3 Fabs, sharpened), EMD-9295 (426cDS-SOSIP D3†-VRC01GL, 3 Fabs, unsharpened), EMD-9304 (426cDS-SOSIP D3†-VRC01GL, 2 fabs, unsharpened), and EMD-9303 (426cDS-SOSIP D3†-VRC01GL, 2 fabs, sharpened). Structures have been deposited to the PDB under accession numbers PDB-6MYY (426cDS-SOSIP D3†-VRC01GL, 3 Fabs]), PDB-6MZJ (426cDS-SOSIP D3†-VRC01GL, 2 fabs), and PDB-6MFT (426c core†-VRC01GL).

The following data sets were generated

Article and author information

Author details

  1. Andrew J Borst

    Department of Biochemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4297-7824
  2. Connor E Weidle

    Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Matthew D Gray

    Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Brandon Frenz

    Department of Biochemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Joost Snijder

    Department of Biochemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. M Gordon Joyce

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Ivelin S Georgiev

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Guillaume BE Stewart-Jones

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Peter D Kwong

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Andrew T McGuire

    Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Frank DiMaio

    Department of Biochemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7524-8938
  12. Leonidas Stamatatos

    Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    For correspondence
    lstamata@fredhutch.org
    Competing interests
    The authors declare that no competing interests exist.
  13. Marie Pancera

    Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    For correspondence
    mpancera@fredhutch.org
    Competing interests
    The authors declare that no competing interests exist.
  14. David Veesler

    Department of Biochemistry, University of Washington, Seattle, United States
    For correspondence
    dveesler@uw.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6019-8675

Funding

National Institute of General Medical Sciences (R01GM120553)

  • David Veesler

National Institute of Allergy and Infectious Diseases (R01AI081625)

  • Leonidas Stamatatos

Pew Charitable Trusts

  • David Veesler

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

Reviewing Editor

  1. Pamela J Bjorkman, California Institute of Technology, United States

Version history

  1. Received: April 18, 2018
  2. Accepted: October 11, 2018
  3. Accepted Manuscript published: November 7, 2018 (version 1)
  4. Version of Record published: November 15, 2018 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Andrew J Borst
  2. Connor E Weidle
  3. Matthew D Gray
  4. Brandon Frenz
  5. Joost Snijder
  6. M Gordon Joyce
  7. Ivelin S Georgiev
  8. Guillaume BE Stewart-Jones
  9. Peter D Kwong
  10. Andrew T McGuire
  11. Frank DiMaio
  12. Leonidas Stamatatos
  13. Marie Pancera
  14. David Veesler
(2018)
Germline VRC01 antibody recognition of a modified clade C HIV-1 envelope trimer and a glycosylated HIV-1 gp120 core
eLife 7:e37688.
https://doi.org/10.7554/eLife.37688

Share this article

https://doi.org/10.7554/eLife.37688

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