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Digoxin reveals a functional connection between HIV-1 integration preference and T-cell activation
HIV-1 integrates more frequently into transcribed genes, however the biological significance of HIV-1 integration targeting has remained elusive. Using a selective high-throughput chemical screen, we discovered that the cardiac glycoside digoxin inhibits wild-type HIV-1 infection more potently than...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519191/ https://www.ncbi.nlm.nih.gov/pubmed/28727807 http://dx.doi.org/10.1371/journal.ppat.1006460 |
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author | Zhyvoloup, Alexander Melamed, Anat Anderson, Ian Planas, Delphine Lee, Chen-Hsuin Kriston-Vizi, Janos Ketteler, Robin Merritt, Andy Routy, Jean-Pierre Ancuta, Petronela Bangham, Charles R. M. Fassati, Ariberto |
author_facet | Zhyvoloup, Alexander Melamed, Anat Anderson, Ian Planas, Delphine Lee, Chen-Hsuin Kriston-Vizi, Janos Ketteler, Robin Merritt, Andy Routy, Jean-Pierre Ancuta, Petronela Bangham, Charles R. M. Fassati, Ariberto |
author_sort | Zhyvoloup, Alexander |
collection | PubMed |
description | HIV-1 integrates more frequently into transcribed genes, however the biological significance of HIV-1 integration targeting has remained elusive. Using a selective high-throughput chemical screen, we discovered that the cardiac glycoside digoxin inhibits wild-type HIV-1 infection more potently than HIV-1 bearing a single point mutation (N74D) in the capsid protein. We confirmed that digoxin repressed viral gene expression by targeting the cellular Na(+)/K(+) ATPase, but this did not explain its selectivity. Parallel RNAseq and integration mapping in infected cells demonstrated that digoxin inhibited expression of genes involved in T-cell activation and cell metabolism. Analysis of >400,000 unique integration sites showed that WT virus integrated more frequently than N74D mutant within or near genes susceptible to repression by digoxin and involved in T-cell activation and cell metabolism. Two main gene networks down-regulated by the drug were CD40L and CD38. Blocking CD40L by neutralizing antibodies selectively inhibited WT virus infection, phenocopying digoxin. Thus the selectivity of digoxin depends on a combination of integration targeting and repression of specific gene networks. The drug unmasked a functional connection between HIV-1 integration and T-cell activation. Our results suggest that HIV-1 evolved integration site selection to couple its early gene expression with the status of target CD4+ T-cells, which may affect latency and viral reactivation. |
format | Online Article Text |
id | pubmed-5519191 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-55191912017-08-07 Digoxin reveals a functional connection between HIV-1 integration preference and T-cell activation Zhyvoloup, Alexander Melamed, Anat Anderson, Ian Planas, Delphine Lee, Chen-Hsuin Kriston-Vizi, Janos Ketteler, Robin Merritt, Andy Routy, Jean-Pierre Ancuta, Petronela Bangham, Charles R. M. Fassati, Ariberto PLoS Pathog Research Article HIV-1 integrates more frequently into transcribed genes, however the biological significance of HIV-1 integration targeting has remained elusive. Using a selective high-throughput chemical screen, we discovered that the cardiac glycoside digoxin inhibits wild-type HIV-1 infection more potently than HIV-1 bearing a single point mutation (N74D) in the capsid protein. We confirmed that digoxin repressed viral gene expression by targeting the cellular Na(+)/K(+) ATPase, but this did not explain its selectivity. Parallel RNAseq and integration mapping in infected cells demonstrated that digoxin inhibited expression of genes involved in T-cell activation and cell metabolism. Analysis of >400,000 unique integration sites showed that WT virus integrated more frequently than N74D mutant within or near genes susceptible to repression by digoxin and involved in T-cell activation and cell metabolism. Two main gene networks down-regulated by the drug were CD40L and CD38. Blocking CD40L by neutralizing antibodies selectively inhibited WT virus infection, phenocopying digoxin. Thus the selectivity of digoxin depends on a combination of integration targeting and repression of specific gene networks. The drug unmasked a functional connection between HIV-1 integration and T-cell activation. Our results suggest that HIV-1 evolved integration site selection to couple its early gene expression with the status of target CD4+ T-cells, which may affect latency and viral reactivation. Public Library of Science 2017-07-20 /pmc/articles/PMC5519191/ /pubmed/28727807 http://dx.doi.org/10.1371/journal.ppat.1006460 Text en © 2017 Zhyvoloup et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Zhyvoloup, Alexander Melamed, Anat Anderson, Ian Planas, Delphine Lee, Chen-Hsuin Kriston-Vizi, Janos Ketteler, Robin Merritt, Andy Routy, Jean-Pierre Ancuta, Petronela Bangham, Charles R. M. Fassati, Ariberto Digoxin reveals a functional connection between HIV-1 integration preference and T-cell activation |
title | Digoxin reveals a functional connection between HIV-1 integration preference and T-cell activation |
title_full | Digoxin reveals a functional connection between HIV-1 integration preference and T-cell activation |
title_fullStr | Digoxin reveals a functional connection between HIV-1 integration preference and T-cell activation |
title_full_unstemmed | Digoxin reveals a functional connection between HIV-1 integration preference and T-cell activation |
title_short | Digoxin reveals a functional connection between HIV-1 integration preference and T-cell activation |
title_sort | digoxin reveals a functional connection between hiv-1 integration preference and t-cell activation |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519191/ https://www.ncbi.nlm.nih.gov/pubmed/28727807 http://dx.doi.org/10.1371/journal.ppat.1006460 |
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