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

Autor: Yang Z; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA., Dam KA; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA., Bridges MD; Jules Stein Eye Institute, University of California, Los Angeles, CA, USA.; Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA., Hoffmann MAG; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA., DeLaitsch AT; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA., Gristick HB; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA., Escolano A; Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, USA., Gautam R; Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Martin MA; Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Nussenzweig MC; Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, USA.; Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA., Hubbell WL; Jules Stein Eye Institute, University of California, Los Angeles, CA, USA.; Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA., Bjorkman PJ; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA. bjorkman@caltech.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Feb 08; Vol. 13 (1), pp. 732. Date of Electronic Publication: 2022 Feb 08.
DOI: 10.1038/s41467-022-28424-3
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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