Jonathan Richard, Michael W. Grunst, Ling Niu, Marco A. Díaz-Salinas, Li Zhu, William D. 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, A. Morton, Rick Huang, Doreen Matthies, Amos B. Smith, Priti Kumar, Walther Mothes, James B. Munro, Marzena Pazgier, Andrés Finzi
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. When administrated along with the anti-CoRBS 17b, CJF-III-288 delayed viral rebound after ART interruption in HIV-1-infected humanized mice, demonstrating potential for eliciting ADCC in vivo. Structural and conformational analyses reveal that CJF-III-288, in combination with this 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.