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 A. Díaz-Salinas, Li Zhu, William D. Tolbert, Lorie Marchitto, Fei Zhou, Catherine Bourassa, Hongil 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 (), Walther Mothes (), James B. Munro (), Marzena Pazgier () and Andrés Finzi ()
Additional contact information
Jonathan Richard: Centre de Recherche du CHUM
Michael W. Grunst: Yale University School of Medicine, Department of Microbial Pathogenesis
Ling Niu: Uniformed Services University of the Health Sciences, Infectious Diseases Division, Department of Medicine
Marco A. Díaz-Salinas: University of Massachusetts Chan Medical School, Department of Microbiology
Li Zhu: Yale University School of Medicine, Department of Internal Medicine, Section of Infectious Diseases
William D. Tolbert: Uniformed Services University of the Health Sciences, Infectious Diseases Division, Department of Medicine
Lorie Marchitto: Centre de Recherche du CHUM
Fei Zhou: NIH, Unit on Structural Biology, Division of Basic and Translational Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Catherine Bourassa: Centre de Recherche du CHUM
Hongil Kim: Yale University School of Medicine, Department of Internal Medicine, Section of Infectious Diseases
Sri Lakshmi Tejaswi Boodapati: Yale University School of Medicine, Department of Internal Medicine, Section of Infectious Diseases
Derek Yang: University of Pennsylvania, Department of Chemistry, School of Arts and Sciences
Ta Jung Chiu: University of Pennsylvania, Department of Chemistry, School of Arts and Sciences
Hung-Ching Chen: University of Pennsylvania, Department of Chemistry, School of Arts and Sciences
Mehdi Benlarbi: Centre de Recherche du CHUM
Guillaume Beaudoin-Bussières: Centre de Recherche du CHUM
Suneetha Gottumukkala: Uniformed Services University of the Health Sciences, Infectious Diseases Division, Department of Medicine
Wenwei Li: Yale University School of Medicine, Department of Microbial Pathogenesis
Katrina Dionne: Centre de Recherche du CHUM
Étienne Bélanger: Centre de Recherche du CHUM
Debashree Chatterjee: Centre de Recherche du CHUM
Halima Medjahed: Centre de Recherche du CHUM
Wayne A. Hendrickson: Columbia University, Department of Biochemistry and Molecular Biophysics
Joseph Sodroski: Dana-Farber Cancer Institute, Department of Cancer Immunology and Virology
Zabrina C. Lang: Laboratory of Cell Biology, National Cancer Institute, NIH
Abraham J. Morton: Laboratory of Cell Biology, National Cancer Institute, NIH
Rick K. Huang: Laboratory of Cell Biology, National Cancer Institute, NIH
Doreen Matthies: NIH, Unit on Structural Biology, Division of Basic and Translational Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Amos B. Smith: University of Pennsylvania, Department of Chemistry, School of Arts and Sciences
Priti Kumar: Yale University School of Medicine, Department of Internal Medicine, Section of Infectious Diseases
Walther Mothes: Yale University School of Medicine, Department of Microbial Pathogenesis
James B. Munro: University of Massachusetts Chan Medical School, Department of Microbiology
Marzena Pazgier: Uniformed Services University of the Health Sciences, Infectious Diseases Division, Department of Medicine
Andrés Finzi: Centre de Recherche du CHUM

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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. 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.

Date: 2025
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DOI: 10.1038/s41467-025-65866-x

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