The asymmetric opening of HIV-1 Env by a potent CD4 mimetic enables anti-coreceptor binding site antibodies to mediate ADCC

Jonathan Richard; Michael W. Grunst; Ling Niu; Marco Aurelio Díaz-Salinas; Li Zhu; William David Tolbert; Lorie Marchitto; Fei Zhou; Catherine Bourassa; H.O. Kim; Sri Lakshmi Tejaswi Boodapati; Derek Yang; Ta-Jung Chiu; Hung-Ching Chen; Mehdi Benlarbi; Guillaume Beaudoin-Bussières; Suneetha Gottumukkala; Wenwei Li; Katrina Dionne; Étienne Bélanger; Debashree Chatterjee; Halima Medjahed; Wayne A. Hendrickson; Joseph Sodroski; Zabrina C. Lang; Abraham J. Morton; Rick K Huang; Doreen Matthies; Amos B. Smith; Priti Kumar

doi:10.1038/s41467-025-65866-x

MicrobiologyNature CommunicationsDec 1, 2025

Peer-reviewed journal article

The asymmetric opening of HIV-1 Env by a potent CD4 mimetic enables anti-coreceptor binding site antibodies to mediate ADCC

Jonathan Richard iD, Michael W. Grunst iD, Ling Niu, Marco Aurelio Díaz-Salinas iD, Li Zhu iD, William David Tolbert iD, Lorie Marchitto iD, Fei Zhou, Catherine Bourassa iD, H.O. Kim iD, Sri Lakshmi Tejaswi Boodapati iD, Derek Yang iD, Ta-Jung Chiu iD, Hung-Ching Chen iD, Mehdi Benlarbi iD, Guillaume Beaudoin-Bussières iD, Suneetha Gottumukkala, Wenwei Li iD, Katrina Dionne, Étienne Bélanger, Debashree Chatterjee iD, Halima Medjahed, Wayne A. Hendrickson iD, Joseph Sodroski iD, Zabrina C. Lang iD, , Andrés Finzi iD

Abstract

HIV-1 envelope glycoproteins (Env) from primary HIV-1 isolates typically adopt a pretriggered "closed" conformation that resists to CD4-induced (CD4i) non-neutralizing antibodies (nnAbs) mediating antibody-dependent cellular cytotoxicity (ADCC). CD4-mimetic compounds (CD4mcs) "open-up" Env allowing binding of CD4i nnAbs, thereby sensitizing HIV-1-infected cells to ADCC. Two families of CD4i nnAbs, the anti-cluster A and anti-coreceptor binding site (CoRBS) Abs, are required to mediate ADCC in combination with the indane CD4mc BNM-III-170. Recently, new indoline CD4mcs with improved potency and breadth have been described. Here, we show that the lead indoline CD4mc, CJF-III-288, sensitizes HIV-1-infected cells to ADCC mediated by anti-CoRBS Abs alone, contributing to improved ADCC activity. Structural and conformational analyses reveal that CJF-III-288, in combination with anti-CoRBS Abs, potently stabilizes an asymmetric "open" State-3 Env conformation, This Env conformation orients the anti-CoRBS Ab to improve ADCC activity and therapeutic potential.

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