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

Author

Listed:
  • Zhi Yang

    (California Institute of Technology)

  • Kim-Marie A. Dam

    (California Institute of Technology)

  • Michael D. Bridges

    (Jules Stein Eye Institute, University of California
    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
    The Rockefeller University)

  • Wayne L. Hubbell

    (Jules Stein Eye Institute, University of California
    University of California)

  • Pamela J. Bjorkman

    (California Institute of Technology)

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.

Suggested Citation

  • 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, 2022. "Neutralizing antibodies induced in immunized macaques recognize the CD4-binding site on an occluded-open HIV-1 envelope trimer," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28424-3
    DOI: 10.1038/s41467-022-28424-3
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