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

Nat Commun. 2022-02; 
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, Pamela J Bjorkman
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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 bridgin... More