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Neutralizing antibodies induced in immunized macaques recognize the CD4-binding site on an occluded-open HIV-1 envelope trimer

Yang, Zhi and Dam, Kim-Marie A. and Bridges, Michael D. and Hoffmann, Magnus A. G. and DeLaitsch, Andrew T. and Gristick, Harry B. and Escolano, Amelia and Gautam, Rajeev and Martin, Malcolm A. and Nussenzweig, Michel C. and Hubbell, Wayne L. and Bjorkman, Pamela J. (2022) Neutralizing antibodies induced in immunized macaques recognize the CD4-binding site on an occluded-open HIV-1 envelope trimer. Nature Communications, 13 . Art. No. 732. ISSN 2041-1723. PMCID PMC8826976. doi:10.1038/s41467-022-28424-3.

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Broadly-neutralizing antibodies (bNAbs) against HIV-1 Env can protect from infection. We characterize Ab1303 and Ab1573, heterologously-neutralizing CD4-binding site (CD4bs) antibodies, isolated from sequentially-immunized macaques. Ab1303/Ab1573 binding is observed only when Env trimers are not constrained in the closed, prefusion conformation. Fab-Env cryo-EM structures show that both antibodies recognize the CD4bs on Env trimer with an ‘occluded-open’ conformation between closed, as targeted by bNAbs, and fully-open, as recognized by CD4. The occluded-open Env trimer conformation includes outwardly-rotated gp120 subunits, but unlike CD4-bound Envs, does not exhibit V1V2 displacement, 4-stranded gp120 bridging sheet, or co-receptor binding site exposure. Inter-protomer distances within trimers measured by double electron-electron resonance spectroscopy suggest an equilibrium between occluded-open and closed Env conformations, consistent with Ab1303/Ab1573 binding stabilizing an existing conformation. Studies of Ab1303/Ab1573 demonstrate that CD4bs neutralizing antibodies that bind open Env trimers can be raised by immunization, thereby informing immunogen design and antibody therapeutic efforts.

Item Type:Article
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URLURL TypeDescription CentralArticle Paper
Yang, Zhi0000-0001-8680-3784
Dam, Kim-Marie A.0000-0002-1416-4757
Bridges, Michael D.0000-0001-9999-9106
Hoffmann, Magnus A. G.0000-0003-4923-9568
DeLaitsch, Andrew T.0000-0002-3458-3449
Gristick, Harry B.0000-0002-1957-2821
Escolano, Amelia0000-0002-1945-2440
Gautam, Rajeev0000-0003-2390-8727
Martin, Malcolm A.0000-0002-6845-9905
Nussenzweig, Michel C.0000-0003-0592-8564
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© The Author(s) 2022. 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 Received 07 October 2021; Accepted 24 January 2022; Published 08 February 2022. We thank Anthony P. West (Caltech) for help with analysis of antibody 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 Gordon and Betty Moore and Beckman Foundations for gifts to Caltech to support the Molecular Observatory (Dr. Jens Kaiser, director) and the beamline staff at SSRL for data collection assistance. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-c76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (P41GM103393). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. We thank Jost Vielmetter and Pauline Hoffman at the Beckman Institute Protein Expression Center at Caltech for protein production, John Moore (Weill Cornell Medical College) for the BG505 stable cell line, 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 for sorting. 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.A.M., and M.C.N.), the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. (R.G. and M.A.M), NIH P50 AI150464 (P.J.B.). M.C.N. is an HHMI Investigator. Data availability: The atomic models generated in this study have been deposited in the Protein Data Bank (PDB) under accession codes 7RYU and 7RYV for Ab1303 Fab and Ab1573 Fab X-ray crystal structures, respectively. The cryo-EM maps and atomic coordinates have been deposited in the Electron Microscopy Data Bank (EMDB) and Protein Data Bank with accession codes EMD-25877 and PDB 7TFN for Ab1303-BG505 complex, and EMD-25878 and PDB 7TFO for Ab1573-BG505 complex. Source data are provided with this paper. Author Contributions: Z.Y., K.A.D., M.A.M., M.C.N., W.L.H., and P.J.B. designed the research. Z.Y., K.A.D., M.D.B., M.A.G.H., H.B.G., A.T.D, A.E., and R.G. performed experiments and analyzed results. Z.Y., K.A.D., M.D.B., and P.J.B. wrote the paper with input from co-authors. The authors declare no competing interests. Peer review information: Nature Communications thanks the anonymous reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.
Funding AgencyGrant Number
Department of Energy (DOE)DE-AC02-C76SF00515
NIHP01 AI100148
Bill and Melinda Gates FoundationINV-002143
NIHP50 AI150464
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Subject Keywords:Cryoelectron microscopy; Immunology; Proteins; Viral host response
PubMed Central ID:PMC8826976
Record Number:CaltechAUTHORS:20211105-225407818
Persistent URL:
Official Citation:Yang, Z., Dam, KM.A., Bridges, M.D. et al. Neutralizing antibodies induced in immunized macaques recognize the CD4-binding site on an occluded-open HIV-1 envelope trimer. Nat Commun 13, 732 (2022).
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:111781
Deposited By: Tony Diaz
Deposited On:08 Nov 2021 21:41
Last Modified:07 Apr 2022 15:55

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