Development of antibody-dependent cell cytotoxicity function in HIV-1 antibodies
- Fred Hutchinson Cancer Research Center, United States
- University of Washington, United States
- University of Nairobi, Kenya
- 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.
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Subject QA255 antibody sequencingNCBI BioProject, PRJNA639297.
Article and author information
Author details
Frederick A Matsen IV
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.
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.
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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Development of antibody-dependent cell cytotoxicity function in HIV-1 antibodies
eLife 10:e63444.
https://doi.org/10.7554/eLife.63444
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