Structure-function analyses reveal key molecular determinants of HIV-1 CRF01_AE resistance to the entry inhibitor temsavir
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Published:2023-10-23
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Prévost Jérémie, Chen YaozongORCID, Zhou Fei, Tolbert William D.ORCID, Gasser RomainORCID, Medjahed Halima, Nayrac ManonORCID, Nguyen Dung N., Gottumukkala Suneetha, Hessell Ann J.ORCID, Rao Venigalla B.ORCID, Pozharski Edwin, Huang Rick K., Matthies DoreenORCID, Finzi Andrés, Pazgier Marzena
Abstract
AbstractThe 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.
Funder
Division of Intramural Research, National Institute of Allergy and Infectious Diseases U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre ViiV Healthcare
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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