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

Yang, Zhi; Dam, Kim-Marie A.; Bridges, Michael D.; Hoffmann, Magnus A. G.; DeLaitsch, Andrew T.; Gristick, Harry B.; Escolano, Amelia; Gautam, Rajeev; Martin, Malcolm A.; Nussenzweig, Michel C.; Hubbell, Wayne L.; Bjorkman, Pamela J.

doi:10.1038/s41467-022-28424-3

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

Journal Article · Tue Feb 08 04:00:00 EST 2022 · Nature Communications

DOI:https://doi.org/10.1038/s41467-022-28424-3· OSTI ID:1982102

Yang, Zhi ^[1]; ^[1]; Bridges, Michael D. ^[2]; ^[1]; ^[1]; Gristick, Harry B. ^[1]; Escolano, Amelia ^[3]; Gautam, Rajeev ^[4]; Martin, Malcolm A. ^[4]; Nussenzweig, Michel C. ^[5]; Hubbell, Wayne L. ^[2]; ^[1]

California Institute of Technology (CalTech), Pasadena, CA (United States)
Univ. of California, Los Angeles, CA (United States)
Rockefeller Univ., New York, NY (United States)
National Institutes of Health (NIH), Bethesda, MD (United States). National Institute of Allergy and Infectious Diseases
Rockefeller Univ., New York, NY (United States). Howard Hughes Medical Institute

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.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory, Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); National Institute of General Medical Sciences (NIGMS); National Institute of Allergy and Infectious Diseases (NIAID); Gates CAVD

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1982102

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 13; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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