Development of antibody-dependent cell cytotoxicity function in HIV-1 antibodies

  1. Laura E Doepker
  2. Sonja Danon
  3. Elias Harkins
  4. Duncan K Ralph
  5. Zak Yaffe
  6. Meghan E Garrett
  7. Amrit Dhar
  8. Cassia Wagner
  9. Megan M Stumpf
  10. Dana Arenz
  11. James A Williams
  12. Walter Jaoko
  13. Kishor Mandaliya
  14. Kelly K Lee
  15. Frederick A Matsen IV
  16. Julie M Overbaugh  Is a corresponding author
  1. Fred Hutchinson Cancer Research Center, United States
  2. University of Washington, United States
  3. University of Nairobi, Kenya
  4. Coast Provincial General Hospital, Kenya

Abstract

A prerequisite for the design of an HIV vaccine that elicits protective antibodies is understanding the developmental pathways that result in desirable antibody features. The development of antibodies that mediate antibody-dependent cellular cytotoxicity (ADCC) is particularly relevant because such antibodies have been associated with HIV protection in humans. We reconstructed the developmental pathways of six human HIV-specific ADCC antibodies using longitudinal antibody sequencing data. Most of the inferred naïve antibodies did not mediate detectable ADCC. Gain of antigen binding and ADCC function typically required mutations in complementarity determining regions of one or both chains. Enhancement of ADCC potency often required additional mutations in framework regions. Antigen binding affinity and ADCC activity were correlated, but affinity alone was not sufficient to predict ADCC potency. Thus, elicitation of broadly active ADCC antibodies may require mutations that enable high affinity antigen recognition along with mutations that optimize factors contributing to functional ADCC activity.

Data availability

Sequencing data have been deposited in BioProject SRA under the accession codes PRJNA639297 and PRJNA685289. Data generated and analyzed in this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 2, 4, 5, 7, and 8.

The following data sets were generated

Article and author information

Author details

  1. 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
  2. Sonja Danon

    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:" 0000-0002-5399-7081
  3. Elias Harkins

    Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    No competing interests declared.
  4. Duncan K Ralph

    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    No competing interests declared.
  5. Zak Yaffe

    Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    No competing interests declared.
  6. Meghan E Garrett

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

    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    No competing interests declared.
  8. Cassia Wagner

    Medical Scientist Training Program, Department of Genome Sciences, University of Washington, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9934-7578
  9. Megan M Stumpf

    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:" 0000-0001-8085-3094
  10. Dana Arenz

    Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    No competing interests declared.
  11. James A Williams

    Medicinal Chemistry, University of Washington, Seattle, United States
    Competing interests
    No competing interests declared.
  12. Walter Jaoko

    Medicinal Microbiology, University of Nairobi, Nairobi, Kenya
    Competing interests
    No competing interests declared.
  13. Kishor Mandaliya

    Women's Health Project, Coast Provincial General Hospital, Mombasa, Kenya
    Competing interests
    No competing interests declared.
  14. Kelly K Lee

    Medicinal Chemistry, Microbiology, University of Washington, Seattle, United States
    Competing interests
    No competing interests declared.
  15. Frederick A Matsen IV

    Public Health 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:" 0000-0003-0607-6025
  16. 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 (R37 AI038518)

  • Julie M Overbaugh

National Institutes of Health (R01 HD103571)

  • Julie M Overbaugh

National Institutes of Health (R01 GM113246)

  • Frederick A Matsen IV

National Institutes of Health (R01 AI146028)

  • Frederick A Matsen IV

National Institutes of Health (T32 AI07140)

  • Laura E Doepker

National Institutes of Health (T32 AI083203)

  • Zak Yaffe

National Institutes of Health (P30 AI027757)

  • Duncan K Ralph

Howard Hughes Medical Institute (Faculty Scholar grant)

  • Frederick A Matsen IV

Simons Foundation (Faculty Scholar grant)

  • Frederick A Matsen IV

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

Reviewing Editor

  1. Satyajit Rath, Indian Institute of Science Education and Research (IISER), India

Ethics

Human subjects: Approval to conduct this study was provided by the ethical review committees of the University of Nairobi Institutional Review Board, the Fred Hutchinson Cancer Research Center Institutional Review Board (protocol 7776), and the University of Washington Institutional Review Board; Clinical Trial Management System Number RG1000880. Study participants provided written informed consent prior to enrollment.

Version history

  1. Received: September 25, 2020
  2. Accepted: January 8, 2021
  3. Accepted Manuscript published: January 11, 2021 (version 1)
  4. Version of Record published: February 15, 2021 (version 2)

Copyright

© 2021, Doepker 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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  1. Laura E Doepker
  2. Sonja Danon
  3. Elias Harkins
  4. Duncan K Ralph
  5. Zak Yaffe
  6. Meghan E Garrett
  7. Amrit Dhar
  8. Cassia Wagner
  9. Megan M Stumpf
  10. Dana Arenz
  11. James A Williams
  12. Walter Jaoko
  13. Kishor Mandaliya
  14. Kelly K Lee
  15. Frederick A Matsen IV
  16. Julie M Overbaugh
(2021)
Development of antibody-dependent cell cytotoxicity function in HIV-1 antibodies
eLife 10:e63444.
https://doi.org/10.7554/eLife.63444

Share this article

https://doi.org/10.7554/eLife.63444

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