1. Microbiology and Infectious Disease
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Functional development of a V3/glycan-specific broadly neutralizing antibody isolated from a case of HIV superinfection

  1. Mackenzie M Shipley
  2. Vidya Mangala Prasad
  3. Laura E Doepker
  4. Adam S Dingens
  5. Duncan K Ralph
  6. Elias Harkins
  7. Amrit Dhar
  8. Dana Arenz
  9. Vrasha Chohan
  10. Haidyn Weight
  11. Kishor Mandaliya
  12. Jesse D Bloom
  13. Frederick Matsen IV
  14. Kelly K Lee  Is a corresponding author
  15. Julie M Overbaugh  Is a corresponding author
  1. Fred Hutchinson Cancer Research Center, United States
  2. University of Washington, United States
  3. Coast Provincial General Hospital, Kenya
Research Article
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Cite this article as: eLife 2021;10:e68110 doi: 10.7554/eLife.68110

Abstract

Stimulating broadly neutralizing antibodies (bnAbs) directly from germline remains a barrier for HIV vaccines. HIV superinfection elicits bnAbs more frequently than single infection, providing clues of how to elicit such responses. We used longitudinal antibody sequencing and structural studies to characterize bnAb development from a superinfection case. BnAb QA013.2 bound initial and superinfecting viral Env, despite its probable naïve progenitor only recognizing the superinfecting strain, suggesting both viruses influenced this lineage. A 4.15 Å cryo-EM structure of QA013.2 bound to native-like trimer showed recognition of V3 signatures (N301/N332 and GDIR). QA013.2 relies less on CDRH3 and more on framework and CDRH1 for affinity and breadth compared to other V3/glycan-specific bnAbs. Antigenic profiling revealed that viral escape was achieved by changes in the structurally-defined epitope and by mutations in V1. These results highlight shared and novel properties of QA013.2 relative to other V3/glycan-specific bnAbs in the setting of sequential, diverse antigens.

Data availability

* Sequencing data have been deposited at BioProject SRA, accession PRJNA674442.* The EM map and atomic coordinates for QA013.2 complexed to BG505.SOSIP.664 are deposited under accession codes EMD-24195 and PDB 7N65.* Source data have been provided for Figures 2-8.

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Article and author information

Author details

  1. Mackenzie M Shipley

    Human Biology, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7436-5622
  2. Vidya Mangala Prasad

    Medicinal Chemistry, Microbiology, University of Washington, Seattle, United States
    Competing interests
    No competing interests declared.
  3. Laura E Doepker

    Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4514-5003
  4. Adam S Dingens

    Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9603-9409
  5. Duncan K Ralph

    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    No competing interests declared.
  6. Elias Harkins

    Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    No competing interests declared.
  7. Amrit Dhar

    Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    No competing interests declared.
  8. Dana Arenz

    Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    No competing interests declared.
  9. Vrasha Chohan

    Human Biology, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    No competing interests declared.
  10. Haidyn Weight

    Human Biology, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    No competing interests declared.
  11. Kishor Mandaliya

    Women's Health Project, Coast Provincial General Hospital, Mombasa, Kenya
    Competing interests
    No competing interests declared.
  12. Jesse D Bloom

    Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1267-3408
  13. Frederick Matsen IV

    Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    No competing interests declared.
  14. Kelly K Lee

    Medicinal Chemistry, Microbiology, University of Washington, Seattle, United States
    For correspondence
    kklee@uw.edu
    Competing interests
    No competing interests declared.
  15. Julie M Overbaugh

    Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    For correspondence
    joverbau@fredhutch.org
    Competing interests
    Julie M Overbaugh, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0239-9444

Funding

National Institutes of Health (R01 AI140891)

  • Jesse D Bloom

National Institutes of Health (R01 AI146028)

  • Frederick Matsen IV

National Institutes of Health (U19 AI117891)

  • Frederick Matsen IV

National Institutes of Health (U19 AI128914)

  • Frederick Matsen IV

National Institutes of Health (R01 AI140868)

  • Kelly K Lee

National Institutes of Health (R01 AI138709)

  • Julie M Overbaugh

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

Ethics

Human subjects: This study (Clinical Trial Management System Number RG1000880) was approved by members of the ethical review committees (file number 7776) at the University of Nairobi, the Fred Hutchinson Cancer Research Center, and the University of Washington. Study participants provided written informed consent prior to enrollment.

Reviewing Editor

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

Publication history

  1. Received: March 5, 2021
  2. Accepted: July 14, 2021
  3. Accepted Manuscript published: July 15, 2021 (version 1)

Copyright

© 2021, Shipley 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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