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

Zhi Yang, Kim-Marie A. Dam, Michael D. Bridges, Magnus A. G. Hoffmann, Andrew T. DeLaitsch, Harry B. Gristick, Amelia Escolano, Rajeev Gautam, Malcolm A. Martin, Michel C. Nussenzweig, Wayne L. Hubbell and Pamela J. Bjorkman ()
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Zhi Yang: California Institute of Technology
Kim-Marie A. Dam: California Institute of Technology
Michael D. Bridges: Jules Stein Eye Institute, University of California
Magnus A. G. Hoffmann: California Institute of Technology
Andrew T. DeLaitsch: California Institute of Technology
Harry B. Gristick: California Institute of Technology
Amelia Escolano: The Rockefeller University
Rajeev Gautam: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Malcolm A. Martin: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Michel C. Nussenzweig: The Rockefeller University
Wayne L. Hubbell: Jules Stein Eye Institute, University of California
Pamela J. Bjorkman: California Institute of Technology

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-28424-3

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