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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
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.
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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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