TY - JOUR
T1 - The asymmetric opening of HIV-1 Env by a potent CD4 mimetic enables anti-coreceptor binding site antibodies to mediate ADCC
AU - Richard, Jonathan
AU - Grunst, Michael W.
AU - Niu, Ling
AU - Díaz-Salinas, Marco A.
AU - Zhu, Li
AU - Tolbert, William D.
AU - Marchitto, Lorie
AU - Zhou, Fei
AU - Bourassa, Catherine
AU - Kim, Hongil
AU - Boodapati, Sri Lakshmi Tejaswi
AU - Yang, Derek
AU - Chiu, Ta Jung
AU - Chen, Hung Ching
AU - Benlarbi, Mehdi
AU - Beaudoin-Bussières, Guillaume
AU - Gottumukkala, Suneetha
AU - Li, Wenwei
AU - Dionne, Katrina
AU - Bélanger, Étienne
AU - Chatterjee, Debashree
AU - Medjahed, Halima
AU - Hendrickson, Wayne A.
AU - Sodroski, Joseph
AU - Lang, Zabrina C.
AU - Morton, Abraham J.
AU - Huang, Rick K.
AU - Matthies, Doreen
AU - Smith, Amos B.
AU - Kumar, Priti
AU - Mothes, Walther
AU - Munro, James B.
AU - Pazgier, Marzena
AU - Finzi, Andrés
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12
Y1 - 2025/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=105023453310&partnerID=8YFLogxK
U2 - 10.1038/s41467-025-65866-x
DO - 10.1038/s41467-025-65866-x
M3 - Article
C2 - 41326374
AN - SCOPUS:105023453310
SN - 2041-1723
VL - 16
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 10419
ER -