Neutralizing antibodies elicited in macaques recognize V3 residues on altered conformations of HIV-1 Env trimer

Creators: DeLaitsch, Andrew T.¹; Keeffe, Jennifer R.¹; Gristick, Harry B.¹; Lee, Juliet A.¹; Ding, Wenge²; Liu, Weimin²; Skelly, Ashwin N.²; Shaw, George M.²; Hahn, Beatrice H.²; Bjorkman, Pamela J.¹

1. California Institute of Technology
2. University of Pennsylvania

Abstract

Eliciting broadly neutralizing antibodies that protect against diverse HIV-1 strains is a primary goal of AIDS vaccine research. We characterized Ab1456 and Ab1271, two heterologously-neutralizing antibodies elicited in non-human primates by priming with an engineered V3-targeting SOSIP Env immunogen and boosting with increasingly native-like SOSIP Envs derived from different strain backgrounds. Structures of Env trimers in complex with these antibodies revealed V3 targeting, but on conformational states of Env distinct from the typical closed, prefusion trimeric SOSIP structure. Env trimers bound by Ab1456 adopted conformations resembling CD4-bound open Env states in the absence of soluble CD4, whereas trimers bound by Ab1271 exhibited a trimer apex-altered conformation to accommodate antibody binding. The finding that elicited antibodies cross-neutralized by targeting altered, non-closed, prefusion Env trimer conformations provides important information about Env dynamics that is relevant for HIV-1 vaccine design aimed at raising antibodies to desired epitopes on closed pre-fusion Env trimers.

Copyright and License

© 2024, The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Acknowledgement

We thank Songye Chen and the Caltech Cryo-EM Center, Anastasiya Oguienko, Morgan Abernathy, Welison Floriano, and Jost Vielmetter and the Caltech Protein Expression Center for experimental and technical support, and Malcolm Martin (NIH) for providing SHIVDH12-V3AD8 and SHIVAD8-EO proviral DNA and the rhesus macaque PMBC-derived SHIVDH12-V3AD8 challenge stock. This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) Grant HIVRAD P01 AI100148 (P.J.B., G.B.S., B.H.H.), R37 AI 150590 (B.H.H.), P01 AI 131251 (G.M.S.), NIH P50 1U54AI170856 (P.J.B.). This work was supported, in whole or in part, by the Bill & Melinda Gates Foundation grant INV-002143 (P.J.B.). 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. A.T.D. was supported by an NSF Graduate Research Fellowship.

Contributions

Conceptualization, A.T.D., J.R.K., H.B.G., G.M.S., B.H.H., P.J.B.; Methodology, A.T.D., W.D., W.L.; Investigation, A.T.D., J.A.L., W.D., W.L., A.N.S.; Writing – Original Draft, A.T.D., B.H.H., P.J.B.; Writing – Review & Editing, A.T.D., J.R.K., H.B.G., J.A.L., A.N.S., B.H.H., P.J.B.; Visualization, A.T.D., W.D.; Supervision and Project Administration, J.R.K., G.M.S., B.H.H., P.J.B.; Funding Acquisition, G.M.S., B.H.H., P.J.B.

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