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

Author

Listed:
  • Jérémie Prévost

    (Centre de Recherche du CHUM
    Université de Montréal)

  • 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
    Université de Montréal)

  • Halima Medjahed

    (Centre de Recherche du CHUM)

  • Manon Nayrac

    (Centre de Recherche du CHUM
    Université de Montréal)

  • 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
    University of Maryland School of Medicine)

  • 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
    Université de Montréal)

  • Marzena Pazgier

    (Uniformed Services University of the Health Sciences)

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.

Suggested Citation

  • 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 Poz, 2023. "Structure-function analyses reveal key molecular determinants of HIV-1 CRF01_AE resistance to the entry inhibitor temsavir," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42500-2
    DOI: 10.1038/s41467-023-42500-2
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    1. Neeti Ananthaswamy & Qianglin Fang & Wadad AlSalmi & Swati Jain & Zhenguo Chen & Thomas Klose & Yingyuan Sun & Yue Liu & Marthandan Mahalingam & Subhash Chand & Sodsai Tovanabutra & Merlin L. Robb & M, 2019. "A sequestered fusion peptide in the structure of an HIV-1 transmitted founder envelope trimer," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    2. Peter D. Kwong & Richard Wyatt & James Robinson & Raymond W. Sweet & Joseph Sodroski & Wayne A. Hendrickson, 1998. "Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody," Nature, Nature, vol. 393(6686), pages 648-659, June.
    3. Maolin Lu & Xiaochu Ma & Luis R. Castillo-Menendez & Jason Gorman & Nirmin Alsahafi & Utz Ermel & Daniel S. Terry & Michael Chambers & Dongjun Peng & Baoshan Zhang & Tongqing Zhou & Nick Reichard & Ke, 2019. "Associating HIV-1 envelope glycoprotein structures with states on the virus observed by smFRET," Nature, Nature, vol. 568(7752), pages 415-419, April.
    4. Yen-Ting Lai & Tao Wang & Sijy O’Dell & Mark K. Louder & Arne Schön & Crystal S. F. Cheung & Gwo-Yu Chuang & Aliaksandr Druz & Bob Lin & Krisha McKee & Dongjun Peng & Yongping Yang & Baoshan Zhang & A, 2019. "Lattice engineering enables definition of molecular features allowing for potent small-molecule inhibition of HIV-1 entry," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
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