3 years ago

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

Anat Melamed, Alexander Zhyvoloup, Robin Ketteler, Petronela Ancuta, Jean-Pierre Routy, Chen-Hsuin Lee, Janos Kriston-Vizi, Charles R. M. Bangham, Andy Merritt, Delphine Planas, Ian Anderson, Ariberto Fassati

by Alexander Zhyvoloup, Anat Melamed, Ian Anderson, Delphine Planas, Chen-Hsuin Lee, Janos Kriston-Vizi, Robin Ketteler, Andy Merritt, Jean-Pierre Routy, Petronela Ancuta, Charles R. M. Bangham, Ariberto Fassati

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 URL: http://journals.plos.org/plosone/article

DOI: 10.1371/journal.ppat.1006460

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