Functional development of a V3/glycan-specific broadly neutralizing antibody isolated from a case of HIV superinfection
- Fred Hutchinson Cancer Research Center, United States
- University of Washington, United States
- Coast Provincial General Hospital, Kenya
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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Subject QA013 antibody sequencingBioProject, PRJNA674442.
Article and author information
Author details
Mackenzie M Shipley
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
- Pamela J Bjorkman, California Institute of Technology, United States
Publication history
- Received: March 5, 2021
- Preprint posted: March 17, 2021 (view preprint)
- Accepted: July 14, 2021
- Accepted Manuscript published: July 15, 2021 (version 1)
- Version of Record published: August 19, 2021 (version 2)
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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Functional development of a V3/glycan-specific broadly neutralizing antibody isolated from a case of HIV superinfection
eLife 10:e68110.
https://doi.org/10.7554/eLife.68110
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