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HIV-1 Escape from Small-Molecule Antagonism of Vif
The HIV-1 accessory protein Vif, which counteracts the antiviral action of the DNA-editing cytidine deaminase APOBEC3G (A3G), is an attractive and yet unexploited therapeutic target. Vif reduces the virion incorporation of A3G by targeting the restriction factor for proteasomal degradation in the vi...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391917/ https://www.ncbi.nlm.nih.gov/pubmed/30808702 http://dx.doi.org/10.1128/mBio.00144-19 |
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author | Sharkey, Mark Sharova, Natalia Mohammed, Idrees Huff, Sarah E. Kummetha, Indrasena Reddy Singh, Gatikrushna Rana, Tariq M. Stevenson, Mario |
author_facet | Sharkey, Mark Sharova, Natalia Mohammed, Idrees Huff, Sarah E. Kummetha, Indrasena Reddy Singh, Gatikrushna Rana, Tariq M. Stevenson, Mario |
author_sort | Sharkey, Mark |
collection | PubMed |
description | The HIV-1 accessory protein Vif, which counteracts the antiviral action of the DNA-editing cytidine deaminase APOBEC3G (A3G), is an attractive and yet unexploited therapeutic target. Vif reduces the virion incorporation of A3G by targeting the restriction factor for proteasomal degradation in the virus-producing cell. Compounds that inhibit Vif-mediated degradation of A3G in cells targeted by HIV-1 would represent a novel antiviral therapeutic. We previously described small molecules with activity consistent with Vif antagonism. In this study, we derived inhibitor escape HIV-1 variants to characterize the mechanism by which these novel agents inhibit virus replication. Here we show that resistance to these agents is dependent on an amino acid substitution in Vif (V142I) and on a point mutation that likely upregulates transcription by modifying the lymphocyte enhancing factor 1 (LEF-1) binding site. Molecular modeling demonstrated a docking site in the Vif-Elongin C complex that is disrupted by these inhibitors. This docking site is lost when Vif acquires the V142I mutation that leads to inhibitor resistance. Competitive fitness experiments indicated that the V142I Vif and LEF-1 binding site mutations created a virus that is better adapted to growing in the presence of A3G than the wild-type virus. |
format | Online Article Text |
id | pubmed-6391917 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-63919172019-03-04 HIV-1 Escape from Small-Molecule Antagonism of Vif Sharkey, Mark Sharova, Natalia Mohammed, Idrees Huff, Sarah E. Kummetha, Indrasena Reddy Singh, Gatikrushna Rana, Tariq M. Stevenson, Mario mBio Research Article The HIV-1 accessory protein Vif, which counteracts the antiviral action of the DNA-editing cytidine deaminase APOBEC3G (A3G), is an attractive and yet unexploited therapeutic target. Vif reduces the virion incorporation of A3G by targeting the restriction factor for proteasomal degradation in the virus-producing cell. Compounds that inhibit Vif-mediated degradation of A3G in cells targeted by HIV-1 would represent a novel antiviral therapeutic. We previously described small molecules with activity consistent with Vif antagonism. In this study, we derived inhibitor escape HIV-1 variants to characterize the mechanism by which these novel agents inhibit virus replication. Here we show that resistance to these agents is dependent on an amino acid substitution in Vif (V142I) and on a point mutation that likely upregulates transcription by modifying the lymphocyte enhancing factor 1 (LEF-1) binding site. Molecular modeling demonstrated a docking site in the Vif-Elongin C complex that is disrupted by these inhibitors. This docking site is lost when Vif acquires the V142I mutation that leads to inhibitor resistance. Competitive fitness experiments indicated that the V142I Vif and LEF-1 binding site mutations created a virus that is better adapted to growing in the presence of A3G than the wild-type virus. American Society for Microbiology 2019-02-26 /pmc/articles/PMC6391917/ /pubmed/30808702 http://dx.doi.org/10.1128/mBio.00144-19 Text en Copyright © 2019 Sharkey et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Sharkey, Mark Sharova, Natalia Mohammed, Idrees Huff, Sarah E. Kummetha, Indrasena Reddy Singh, Gatikrushna Rana, Tariq M. Stevenson, Mario HIV-1 Escape from Small-Molecule Antagonism of Vif |
title | HIV-1 Escape from Small-Molecule Antagonism of Vif |
title_full | HIV-1 Escape from Small-Molecule Antagonism of Vif |
title_fullStr | HIV-1 Escape from Small-Molecule Antagonism of Vif |
title_full_unstemmed | HIV-1 Escape from Small-Molecule Antagonism of Vif |
title_short | HIV-1 Escape from Small-Molecule Antagonism of Vif |
title_sort | hiv-1 escape from small-molecule antagonism of vif |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391917/ https://www.ncbi.nlm.nih.gov/pubmed/30808702 http://dx.doi.org/10.1128/mBio.00144-19 |
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