Send to

Choose Destination
PLoS Pathog. 2017 Jul 20;13(7):e1006460. doi: 10.1371/journal.ppat.1006460. eCollection 2017 Jul.

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

Author information

Division of Infection & Immunity, University College London, London, United Kingdom.
Department of Medicine, Imperial College, St. Mary's Campus, London, United Kingdom.
Department of Microbiology, Infectiology and Immunology, Faculty of Medicine, University of Montreal and the Research Centre of the CHUM, Montreal, Québec, Canada.
MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom.
Centre for Therapeutics Discovery, MRC Technology, Mill Hill, London, United Kingdom.
McGill University Health Centre, Glen site, Montreal, Québec, Canada.


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.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center