IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-42500-2.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-42500-2
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-42500-2?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. 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.
    2. 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.
    3. 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.
    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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Jun Niu & Qi Wang & Wenwen Zhao & Bing Meng & Youwei Xu & Xianfang Zhang & Yi Feng & Qilian Qi & Yanling Hao & Xuan Zhang & Ying Liu & Jiangchao Xiang & Yiming Shao & Bei Yang, 2023. "Structures and immune recognition of Env trimers from two Asia prevalent HIV-1 CRFs," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Hao Zhang & Peng Wang & Nikitas Papangelopoulos & Ying Xu & Alessandro Sette & Philip E Bourne & Ole Lund & Julia Ponomarenko & Morten Nielsen & Bjoern Peters, 2010. "Limitations of Ab Initio Predictions of Peptide Binding to MHC Class II Molecules," PLOS ONE, Public Library of Science, vol. 5(2), pages 1-10, February.
    3. Lingli Kong & Jianfang Liu & Meng Zhang & Zhuoyang Lu & Han Xue & Amy Ren & Jiankang Liu & Jinping Li & Wai Li Ling & Gang Ren, 2023. "Facile hermetic TEM grid preparation for molecular imaging of hydrated biological samples at room temperature," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    4. Yanay Ofran & Burkhard Rost, 2007. "Protein–Protein Interaction Hotspots Carved into Sequences," PLOS Computational Biology, Public Library of Science, vol. 3(7), pages 1-8, July.
    5. Zhi Yang & Kim-Marie A. Dam & Michael D. Bridges & Magnus A. G. Hoffmann & Andrew T. DeLaitsch & Harry B. Gristick & Amelia Escolano & Rajeev Gautam & Malcolm A. Martin & Michel C. Nussenzweig & Wayne, 2022. "Neutralizing antibodies induced in immunized macaques recognize the CD4-binding site on an occluded-open HIV-1 envelope trimer," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    6. Ignacio Fernández & Lasse Toftdal Dynesen & Youna Coquin & Riccardo Pederzoli & Delphine Brun & Ahmed Haouz & Antoine Gessain & Félix A. Rey & Florence Buseyne & Marija Backovic, 2023. "The crystal structure of a simian Foamy Virus receptor binding domain provides clues about entry into host cells," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    7. Bence Bruncsics & Wesley J. Errington & Casim A. Sarkar, 2022. "MVsim is a toolset for quantifying and designing multivalent interactions," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    8. Carsten Magnus & Roland R Regoes, 2010. "Estimating the Stoichiometry of HIV Neutralization," PLOS Computational Biology, Public Library of Science, vol. 6(3), pages 1-11, March.
    9. Hongjun Bai & Eric Lewitus & Yifan Li & Paul V. Thomas & Michelle Zemil & Mélanie Merbah & Caroline E. Peterson & Thujitha Thuraisamy & Phyllis A. Rees & Agnes Hajduczki & Vincent Dussupt & Bonnie Sli, 2024. "Contemporary HIV-1 consensus Env with AI-assisted redesigned hypervariable loops promote antibody binding," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    10. Aliana López de Victoria & Phanourios Tamamis & Chris A Kieslich & Dimitrios Morikis, 2012. "Insights into the Structure, Correlated Motions, and Electrostatic Properties of Two HIV-1 gp120 V3 Loops," PLOS ONE, Public Library of Science, vol. 7(11), pages 1-15, November.
    11. Yang Yang & DeGruttola Victor, 2012. "Resampling-based Methods in Single and Multiple Testing for Equality of Covariance/Correlation Matrices," The International Journal of Biostatistics, De Gruyter, vol. 8(1), pages 1-32, June.
    12. Terrence M Dobrowsky & Brian R Daniels & Robert F Siliciano & Sean X Sun & Denis Wirtz, 2010. "Organization of Cellular Receptors into a Nanoscale Junction during HIV-1 Adhesion," PLOS Computational Biology, Public Library of Science, vol. 6(7), pages 1-14, July.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42500-2. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.