Antibody elicited by HIV-1 immunogen vaccination in macaques displaces Env fusion peptide and destroys a neutralizing epitope
HIV-1 vaccine design aims to develop an immunogen that elicits broadly neutralizing antibodies against a desired epitope, while eliminating responses to off-target regions of HIV-1 Env. We report characterization of Ab1245, an off-target antibody against the Env gp120-gp41 interface, from V3-glycan patch immunogen-primed and boosted macaques. A 3.7 Å cryo-EM structure of an Ab1245-Env complex reveals one Ab1245 Fab binding asymmetrically to Env trimer at the gp120-gp41 interface using its long CDRH3 to mimic regions of gp41. The mimicry includes positioning of a CDRH3 methionine into the gp41 tryptophan clasp, resulting in displacement of the fusion peptide and fusion peptide-proximal region. Despite fusion peptide displacement, Ab1245 is non-neutralizing even at high concentrations, raising the possibility that only two fusion peptides per trimer are required for viral–host membrane fusion. These structural analyses facilitate immunogen design to prevent elicitation of Ab1245-like antibodies that block neutralizing antibodies against the fusion peptide.
© The Author(s) 2021. 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/. Received 26 March 2021; Accepted 01 October 2021; Published 25 October 2021. We thank Anthony P. West for help with the analysis of antibody CDRH3 sequence analyses. Cryo-EM was performed in the Beckman Institute Resource Center for Transmission Electron Microscopy at Caltech with assistance from directors A. Malyutin and S. Chen. We thank the Beckman Institute Protein Expression Center at Caltech for protein production, John Moore (Weill Cornell Medical College) for the BG505 stable cell line, Gabriella Kiss, Sofia Ferreira, and Brenda Watt at Refeyn Ltd. for providing a demonstration model OneMP mass photometer, training, and materials to Caltech, Kristie M. Gordon (The Rockefeller University) for assistance with flow cytometry, and Rogier W. Sanders and Marit J. van Gils (Academisch Medisch Centrum Universiteit van Amsterdam) for providing AviTagged and biotinylated BG505 and B41 SOSIP trimers. This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) HIVRAD P01 AI100148 (to P.J.B. and M.C.N.), Gates CAVD grant INV-002143 (to P.J.B., M.C.N., and M.A.M.), NIH P50 AI150464 (P.J.B.), an NSF Graduate Research Fellowship (to M.E.A.), and a Bill and Melinda Gates Foundation grant (#OPP1146996 to M.S.S.). M.C.N. is an HHMI Investigator. This work was supported, in whole or in part, by the Bill & Melinda Gates Foundation (grant INV-002143). Under the grant conditions of the Gates 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. Data availability: The atomic model and cryo-EM maps have been deposited in the Protein Data Bank (PDB) accession code 7MXE and Electron Microscopy Data Bank (EMDB) entry EMD-24072. Author Contributions: M.E.A. and P.J.B. designed the research. M.E.A., H.B.G., J.V., J.R.K., and Y.E.L. performed biophysical experiments. M.E.A., H.B.G., J.V., J.R.K., and P.J.B. analyzed the results. P.N.P.G. and M.S.S. carried out and supervised in vitro neutralization assays. A.E. and M.C.N. carried out and supervised the derivation of monoclonal antibody sequences and plasmids from NHPs. R.G. and M.A.M. planned and supervised the immunization experiments in NHPs. M.E.A and P.J.B. wrote the manuscript with input from co-authors. Data availability. The atomic model and cryo-EM maps have been deposited in the Protein Data Bank (PDB) accession code 7MXE and Electron Microscopy Data Bank (EMDB) entry EMD-24072. The authors declare no competing interests.
Accepted Version - 2021.03.17.435265v1.full.pdf
Supplemental Material - 41541_2021_387_MOESM1_ESM.pdf
Supplemental Material - 41541_2021_387_MOESM2_ESM.pdf
Published - s41541-021-00387-4.pdf
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