Structure-function analyses reveal key molecular determinants of HIV-1 CRF01_AE resistance to the entry inhibitor temsavir
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 En...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-10-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-42500-2 |
| _version_ | 1797558006204858368 |
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| author | 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 Marzena Pazgier |
| author_facet | 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 Marzena Pazgier |
| author_sort | Jérémie Prévost |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T17:24:19Z |
| format | Article |
| id | doaj.art-5ca0ee97820f4768be0d20e9dea09bbe |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:24:19Z |
| publishDate | 2023-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-5ca0ee97820f4768be0d20e9dea09bbe2023-11-20T10:13:10ZengNature PortfolioNature Communications2041-17232023-10-0114111510.1038/s41467-023-42500-2Structure-function analyses reveal key molecular determinants of HIV-1 CRF01_AE resistance to the entry inhibitor temsavirJérémie Prévost0Yaozong Chen1Fei Zhou2William D. Tolbert3Romain Gasser4Halima Medjahed5Manon Nayrac6Dung N. Nguyen7Suneetha Gottumukkala8Ann J. Hessell9Venigalla B. Rao10Edwin Pozharski11Rick K. Huang12Doreen Matthies13Andrés Finzi14Marzena Pazgier15Centre de Recherche du CHUMInfectious Disease Division, Department of Medicine, Uniformed Services University of the Health SciencesUnit on Structural Biology, Division of Basic and Translational Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of HealthInfectious Disease Division, Department of Medicine, Uniformed Services University of the Health SciencesCentre de Recherche du CHUMCentre de Recherche du CHUMCentre de Recherche du CHUMInfectious Disease Division, Department of Medicine, Uniformed Services University of the Health SciencesInfectious Disease Division, Department of Medicine, Uniformed Services University of the Health SciencesDivision of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Science UniversityDepartment of Biology, the Catholic University of AmericaInstitute for Bioscience and Biotechnology ResearchLaboratory of Cell Biology, National Cancer Institute, National Institutes of HealthUnit on Structural Biology, Division of Basic and Translational Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of HealthCentre de Recherche du CHUMInfectious Disease Division, Department of Medicine, Uniformed Services University of the Health SciencesAbstract 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.https://doi.org/10.1038/s41467-023-42500-2 |
| spellingShingle | 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 Marzena Pazgier Structure-function analyses reveal key molecular determinants of HIV-1 CRF01_AE resistance to the entry inhibitor temsavir Nature Communications |
| title | Structure-function analyses reveal key molecular determinants of HIV-1 CRF01_AE resistance to the entry inhibitor temsavir |
| title_full | Structure-function analyses reveal key molecular determinants of HIV-1 CRF01_AE resistance to the entry inhibitor temsavir |
| title_fullStr | Structure-function analyses reveal key molecular determinants of HIV-1 CRF01_AE resistance to the entry inhibitor temsavir |
| title_full_unstemmed | Structure-function analyses reveal key molecular determinants of HIV-1 CRF01_AE resistance to the entry inhibitor temsavir |
| title_short | Structure-function analyses reveal key molecular determinants of HIV-1 CRF01_AE resistance to the entry inhibitor temsavir |
| title_sort | structure function analyses reveal key molecular determinants of hiv 1 crf01 ae resistance to the entry inhibitor temsavir |
| url | https://doi.org/10.1038/s41467-023-42500-2 |
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