
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.08.27.609961
preprint
1
Article
The asymmetric opening of HIV-1 Env by a potent CD4 mimetic enables anti-coreceptor binding site antibodies to mediate ADCC
Richard Jonathan
Grunst Michael W.
Niu Ling
Díaz-Salinas Marco A.
Tolbert William D.
Marchitto Lorie
Zhou Fei
Bourassa Catherine
Yang Derek
Chiu Ta Jung
Chen Hung-Ching
Benlarbi Mehdi
Guillaume-Beaudoin-Buissières
Gottumukkala Suneetha
Li Wenwei
Dionne Katrina
Bélanger Étienne
Chatterjee Debashree
Medjahed Halima
Hendrickson Wayne A.
Sodroski Joseph
Lang Zabrina C.
Morton Abraham J.
Huang Rick K.
Matthies Doreen http://orcid.org/0000-0001-9221-4484

Smith Amos B.
Mothes Walther
Munro James B. http://orcid.org/0000-0001-7634-4633

Pazgier Marzena
Finzi Andrés
27 8 2024
2024.08.27.609961https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.08.27.609961
nihpp-2024.08.27.609961.pdf
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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