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Digoxin reveals a functional connection between HIV-1 integration preference and T-cell activation

PLoS pathogens, 2017-07, Vol.13 (7), p.e1006460 [Peer Reviewed Journal]

COPYRIGHT 2017 Public Library of Science ;COPYRIGHT 2017 Public Library of Science ;2017 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Zhyvoloup A, Melamed A, Anderson I, Planas D, Lee C-H, Kriston-Vizi J, et al. (2017) Digoxin reveals a functional connection between HIV-1 integration preference and T-cell activation. PLoS Pathog 13(7): e1006460. https://doi.org/10.1371/journal.ppat.1006460 ;Distributed under a Creative Commons Attribution 4.0 International License ;2017 Zhyvoloup et al 2017 Zhyvoloup et al ;2017 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Zhyvoloup A, Melamed A, Anderson I, Planas D, Lee C-H, Kriston-Vizi J, et al. (2017) Digoxin reveals a functional connection between HIV-1 integration preference and T-cell activation. PLoS Pathog 13(7): e1006460. https://doi.org/10.1371/journal.ppat.1006460 ;ISSN: 1553-7374 ;ISSN: 1553-7366 ;EISSN: 1553-7374 ;DOI: 10.1371/journal.ppat.1006460 ;PMID: 28727807

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Title:
Digoxin reveals a functional connection between HIV-1 integration preference and T-cell activation
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
Swanstrom, Ronald
Subjects: Acquired immune deficiency syndrome ; Activation analysis ; AIDS ; Anti-HIV Agents - pharmacology ; Antibodies ; Antigens ; Biology and Life Sciences ; Capsid protein ; CD38 antigen ; CD4 antigen ; CD4-Positive T-Lymphocytes - drug effects ; CD4-Positive T-Lymphocytes - immunology ; CD40L protein ; Cell activation ; Cell metabolism ; Cells, Cultured ; College campuses ; Digoxin ; Digoxin - pharmacology ; Dosage and administration ; Funding ; Gene expression ; Gene mapping ; Gene silencing ; Gene therapy ; Genes ; Genetic aspects ; HIV ; HIV (Viruses) ; HIV Infections - drug therapy ; HIV Infections - immunology ; HIV Infections - virology ; HIV-1 - drug effects ; HIV-1 - genetics ; HIV-1 - physiology ; Human immunodeficiency virus ; Humans ; Immunology ; Infections ; Inhibition ; Integration ; Laboratories ; Latency ; Life Sciences ; Lymphocyte Activation - drug effects ; Lymphocytes ; Lymphocytes T ; Medicine ; Medicine and Health Sciences ; Metabolism ; Mutation ; Na+/K+-exchanging ATPase ; Neutralizing ; Point mutation ; Proteins ; Research and Analysis Methods ; Selectivity ; Site selection ; Supervision ; T cell receptors ; T cells ; Transcription activation ; University colleges ; Virus Integration - drug effects ; Virus Latency - drug effects ; Viruses
Is Part Of: PLoS pathogens, 2017-07, Vol.13 (7), p.e1006460
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.
Publisher: United States: Public Library of Science
Language: English
Identifier: ISSN: 1553-7374
ISSN: 1553-7366
EISSN: 1553-7374
DOI: 10.1371/journal.ppat.1006460
PMID: 28727807
Source: Public Library of Science (PLoS) Journals Open Access
DOAJ Directory of Open Access Journals
Geneva Foundation Free Medical Journals at publisher websites
MEDLINE
PubMed Central
ProQuest Central

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Digoxin reveals a functional connection between HIV-1 integration preference and T-cell activation

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