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

التفاصيل البيبلوغرافية
العنوان: Structure-function analyses reveal key molecular determinants of HIV-1 CRF01_AE resistance to the entry inhibitor temsavir.
المؤلفون: Prévost J; Centre de Recherche du CHUM, Montreal, QC, Canada.; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC, Canada., Chen Y; Infectious Disease Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA., Zhou F; Unit on Structural Biology, Division of Basic and Translational Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA., Tolbert WD; Infectious Disease Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA., Gasser R; Centre de Recherche du CHUM, Montreal, QC, Canada.; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC, Canada., Medjahed H; Centre de Recherche du CHUM, Montreal, QC, Canada., Nayrac M; Centre de Recherche du CHUM, Montreal, QC, Canada.; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC, Canada., Nguyen DN; Infectious Disease Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA., Gottumukkala S; Infectious Disease Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA., Hessell AJ; Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA., Rao VB; Department of Biology, the Catholic University of America, Washington, DC, USA., Pozharski E; Institute for Bioscience and Biotechnology Research, Rockville, MD, 20850, USA.; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA., Huang RK; Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, USA., Matthies D; Unit on Structural Biology, Division of Basic and Translational Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA., Finzi A; Centre de Recherche du CHUM, Montreal, QC, Canada. andres.finzi@umontreal.ca.; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC, Canada. andres.finzi@umontreal.ca., Pazgier M; Infectious Disease Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. marzena.pazgier@usuhs.edu.
المصدر: Nature communications [Nat Commun] 2023 Oct 23; Vol. 14 (1), pp. 6710. Date of Electronic Publication: 2023 Oct 23.
نوع المنشور: Journal Article; Research Support, N.I.H., Intramural; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: HIV-1*/physiology , Anti-HIV Agents*/therapeutic use , HIV Fusion Inhibitors* , HIV Infections*, Humans ; HIV Envelope Protein gp120/genetics
مستخلص: 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.
(© 2023. Springer Nature Limited.)
التعليقات: Update of: bioRxiv. 2023 Apr 17;:. (PMID: 37131729)
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معلومات مُعتمدة: R01 AI148379 United States AI NIAID NIH HHS; P01 AI150471 United States AI NIAID NIH HHS; R01 AI129769 United States AI NIAID NIH HHS; ZIA HD008998 United States ImNIH Intramural NIH HHS; R01 AI150322 United States AI NIAID NIH HHS; P01 GM056550 United States GM NIGMS NIH HHS; R01 AI129801 United States AI NIAID NIH HHS; R01 AI174908 United States AI NIAID NIH HHS; P01 AI162242 United States AI NIAID NIH HHS
المشرفين على المادة: 0 (Anti-HIV Agents)
0 (HIV Fusion Inhibitors)
0 (HIV Envelope Protein gp120)
تواريخ الأحداث: Date Created: 20231023 Date Completed: 20231027 Latest Revision: 20240210
رمز التحديث: 20240210
مُعرف محوري في PubMed: PMC10593844
DOI: 10.1038/s41467-023-42500-2
PMID: 37872202
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-023-42500-2