Structure-function analyses reveal key molecular determinants of HIV-1 CRF01_AE resistance to the entry inhibitor temsavir

Jérémie Prévost, Yaozong Chen, Fei Zhou, William D. Tolbert, Romain Gasser, Halima Medjahed, Manon Nayrac, Dung N. Nguyen, Suneetha Gottumukkala, Ann J. Hessell, Venigalla B. Rao, Edwin Pozharski, Rick K. Huang, Doreen Matthies, Andrés Finzi () and Marzena Pazgier ()
Additional contact information
Jérémie Prévost: Centre de Recherche du CHUM
Yaozong Chen: Uniformed Services University of the Health Sciences
Fei Zhou: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
William D. Tolbert: Uniformed Services University of the Health Sciences
Romain Gasser: Centre de Recherche du CHUM
Halima Medjahed: Centre de Recherche du CHUM
Manon Nayrac: Centre de Recherche du CHUM
Dung N. Nguyen: Uniformed Services University of the Health Sciences
Suneetha Gottumukkala: Uniformed Services University of the Health Sciences
Ann J. Hessell: Oregon Health and Science University
Venigalla B. Rao: the Catholic University of America
Edwin Pozharski: Institute for Bioscience and Biotechnology Research
Rick K. Huang: National Cancer Institute, National Institutes of Health
Doreen Matthies: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Andrés Finzi: Centre de Recherche du CHUM
Marzena Pazgier: Uniformed Services University of the Health Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract The HIV-1 entry inhibitor temsavir prevents the viral receptor CD4 (cluster of differentiation 4) from interacting with the envelope glycoprotein (Env) and blocks its conformational changes. To do this, temsavir relies on the presence of a residue with small side chain at position 375 in Env and is unable to neutralize viral strains like CRF01_AE carrying His375. Here we investigate the mechanism of temsavir resistance and show that residue 375 is not the sole determinant of resistance. At least six additional residues within the gp120 inner domain layers, including five distant from the drug-binding pocket, contribute to resistance. A detailed structure-function analysis using engineered viruses and soluble trimer variants reveals that the molecular basis of resistance is mediated by crosstalk between His375 and the inner domain layers. Furthermore, our data confirm that temsavir can adjust its binding mode to accommodate changes in Env conformation, a property that likely contributes to its broad antiviral activity.

Date: 2023
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DOI: 10.1038/s41467-023-42500-2

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