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; William D Tolbert; Lorie Marchitto; Fei Zhou; Catherine Bourassa; Derek Yang; Ta Jung Chiu; Hung-Ching Chen; Mehdi Benlarbi; Guillaume-Beaudoin-Buissières; 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 3rd; Walther Mothes; James B Munro; Marzena Pazgier; Andrés Finzi

doi:10.1101/2024.08.27.609961

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

bioRxiv [Preprint]. 2024 Aug 27:2024.08.27.609961. doi: 10.1101/2024.08.27.609961.

Authors

Jonathan Richard^{1

2}, Michael W Grunst³, Ling Niu⁴, Marco A Díaz-Salinas⁵, William D Tolbert⁴, Lorie Marchitto^{1

2}, Fei Zhou⁶, Catherine Bourassa¹, Derek Yang⁷, Ta Jung Chiu⁷, Hung-Ching Chen⁷, Mehdi Benlarbi^{1

2}; Guillaume-Beaudoin-Buissières; Suneetha Gottumukkala⁴, Wenwei Li³, Katrina Dionne^{1

2}, Étienne Bélanger^{1

2}, Debashree Chatterjee^{1

2}, Halima Medjahed¹, Wayne A Hendrickson^{8

9}, Joseph Sodroski^{10

11}, Zabrina C Lang¹², Abraham J Morton¹², Rick K Huang¹², Doreen Matthies⁶, Amos B Smith 3rd⁷, Walther Mothes³, James B Munro^{5

13}, Marzena Pazgier⁴, Andrés Finzi^{1

2}

Affiliations

¹ Centre de Recherche du CHUM, Montréal, Québec, Canada.
² Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Québec, Canada.
³ Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA.
⁴ Infectious Diseases Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁵ Department of Microbiology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA.
⁶ Unit on Structural Biology, Division of Basic and Translational Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA.
⁷ Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA.
⁸ Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.
⁹ Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA.
¹⁰ Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
¹¹ Department of Microbiology, Harvard Medical School, Boston, Massachusetts, USA.
¹² Laboratory of Cell Biology, National Cancer Institute, NIH, Bethesda, USA.
¹³ Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA, USA.

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.

Publication types

Preprint

Abstract

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