Mapping essential somatic hypermutations in a CD4-binding site bNAb informs HIV-1 vaccine design
Creators
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1.
California Institute of Technology
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2.
Beth Israel Deaconess Medical Center
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3.
Harvard University
Abstract
HIV-1 broadly neutralizing antibodies (bNAbs) targeting the CD4-binding site (CD4bs) contain rare features that pose challenges to elicit these bNAbs through vaccination. The IOMA class of CD4bs bNAbs includes fewer rare features and somatic hypermutations (SHMs) to achieve broad neutralization, thus presenting a potentially accessible pathway for vaccine-induced bNAb development. Here, we created a library of IOMA variants in which each SHM was individually reverted to the inferred germline counterpart to investigate the roles of SHMs in conferring IOMA's neutralization potency and breadth. Impacts on neutralization for each variant were evaluated, and this information was used to design minimally mutated IOMA-class variants (IOMAmin) that incorporated the fewest SHMs required for achieving IOMA's neutralization breadth. A cryoelectron microscopy (cryo-EM) structure of an IOMAmin variant bound to Env was used to further interpret characteristics of IOMA variants to elucidate how IOMA's structural features correlate with its neutralization mechanism, informing the design of IOMA-targeting immunogens.
Copyright and License
© 2025 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Acknowledgement
We thank J. Vielmetter, A. Rorick, K. Storm, A. Lam, and the Protein Expression Center in the Beckman Institute at Caltech for assistance with expression and Z. Wu and J. Keeffe for help with polyreactivity assays. Electron microscopy was performed in the Caltech Cryo-EM Center with assistance from S. Chen. This work was supported by the National Institute of Allergy and Infectious Diseases Grant HIVRAD P01 AI100148 (P.J.B.) and NIH 1U54AI170856 (P.J.B.). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIAID or NIH. This work was also supported in part by the Bill & Melinda Gates Foundation grants INV-002143 (P.J.B.) and INV-036842 (M.S.S.). Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 Generic License has already been assigned to the Author Accepted Manuscript version that might arise from this submission.
Funding
This work was supported by the National Institute of Allergy and Infectious Diseases Grant HIVRAD P01 AI100148 (P.J.B.) and NIH 1U54AI170856 (P.J.B.). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIAID or NIH. This work was also supported in part by the Bill & Melinda Gates Foundation grants INV-002143 (P.J.B.) and INV-036842 (M.S.S.). Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 Generic License has already been assigned to the Author Accepted Manuscript version that might arise from this submission.
Contributions
Conceptualization, K.A.D., H.B.G., and P.J.B.; methodology, K.A.D., Y.E.L., Z.Y., P.N.P.G., and M.S.S.; formal analysis, K.A.D. and A.P.W., Jr.; investigation, K.A.D., Y.E.L., Z.Y., P.N.P.G., and M.S.S.; resources, M.S.S. and P.J.B.; data curation, K.A.D. and Z.Y.; writing – original draft, K.A.D. and P.J.B.; writing – review and editing, K.A.D., H.B.G., A.P.W., Jr., M.S.S., and P.J.B.; visualization, K.A.D.; supervision, K.A.D., H.B.G., and P.J.B.; project administration, K.A.D. and P.J.B.; funding acquisition, M.S.S. and P.J.B.
Data Availability
Cryo-EM maps and atomic structures were deposited in the Protein DataBank (PDB) and Electron Microscopy DataBank under accession codes 9EHL and EMD-48059 for the structure of IOMAmin5–BG505–10-1074 class I and under accession codes 9EHM and EMD-48060 for the structure of IOMAmin5–BG505–10-1074 class II.
Conflict of Interest
The authors declare no competing interests.
Supplemental Material
Files
PIIS221112472500484X.pdf
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Additional details
Identifiers
- PMID
- 40378041
- PMCID
- PMC12117015
Related works
- Describes
- Journal Article: 40378041 (PMID)
- Journal Article: PMC12117015 (PMCID)
- Is new version of
- Discussion Paper: 10.1101/2024.11.26.625503 (DOI)
Funding
- National Institute of Allergy and Infectious Diseases
- HIVRAD P01 AI100148
- National Institute of Allergy and Infectious Diseases
- 1U54AI170856
- Bill & Melinda Gates Foundation
- INV-002143
- Bill & Melinda Gates Foundation
- INV-036842
Dates
- Submitted
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2024-12-12
- Updated
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2025-03-17
- Accepted
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2025-04-25
- Available
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2025-05-15Published online