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Antibody elicited by HIV-1 immunogen vaccination in macaques displaces Env fusion peptide and destroys a neutralizing epitope

Abernathy, Morgan E. and Gristick, Harry B. and Vielmetter, Jost and Keeffe, Jennifer R. and Gnanapragasam, Priyanthi N. P. and Lee, Yu E. and Escolano, Amelia and Gautam, Rajeev and Seaman, Michael S. and Martin, Malcolm A and Nussenzweig, Michel C. and Bjorkman, Pamela J. (2021) Antibody elicited by HIV-1 immunogen vaccination in macaques displaces Env fusion peptide and destroys a neutralizing epitope. . (Unpublished)

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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. Here we report isolation and 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, implying 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.

Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper
Gristick, Harry B.0000-0002-1957-2821
Vielmetter, Jost0000-0002-4314-7163
Keeffe, Jennifer R.0000-0002-5317-6398
Nussenzweig, Michel C.0000-0003-0592-8564
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license. This version posted March 17, 2021. We thank Anthony P. West for help with analysis of antibody CDRH3 sequences. 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.), 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. 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.NP.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.
Funding AgencyGrant Number
NIHP01 AI100148
Bill and Melinda Gates FoundationINV-002143
NSF Graduate Research FellowshipUNSPECIFIED
Bill and Melinda Gates FoundationOPP1146996
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Record Number:CaltechAUTHORS:20210318-102454948
Persistent URL:
Official Citation:Antibody elicited by HIV-1 immunogen vaccination in macaques displaces Env fusion peptide and destroys a neutralizing epitope. Morgan E Abernathy, Harry B Gristick, Jost Vielmetter, Jennifer R Keeffe, Priyanthi NP Gnanapragasam, Yu E Lee, Amelia Escolano, Rajeev Gautam, Michael S Seaman, Malcolm A Martin, Michel C Nussenzweig, Pamela J Bjorkman. bioRxiv 2021.03.17.435265; doi:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:108478
Deposited By: Tony Diaz
Deposited On:19 Mar 2021 02:19
Last Modified:19 Apr 2021 22:06

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