ArticlePLoS pathogens2017
Digoxin reveals a functional connection between HIV-1 integration preference and T-cell activation.
Article in PLoS pathogens, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 29 citations in OpenAlex.
- A tissue microenvironment analogous to certain tumor microenvironments facilitates HIV persistence.Frontiers in immunology · 2026Article
- From network biology to immunity: potential longitudinal biomarkers for targeting the network topology of the HIV reservoir.Journal of translational medicine · 2025Review
- Heat shock protein 90 is a chaperone regulator of HIV-1 latency.PLoS pathogens · 2025Article
- The capsid revolution.Journal of molecular cell biology · 2024Review
- Cardiac glycosides inhibit early and late vaccinia virus protein expression.The Journal of general virology · 2024Article
- Unraveling the palindromic and nonpalindromic motifs of retroviral integration site sequences by statistical mixture models.Genome research · 2023Article
- Article
- Research Progress in Pharmacological Activities and Applications of Cardiotonic Steroids.Frontiers in pharmacology · 2022Review
- Depth of the Steroid Core Location Determines the Mode of Na,K-ATPase Inhibition by Cardiotonic Steroids.International journal of molecular sciences · 2021Article
- Th17 cell master transcription factor RORC2 regulates HIV-1 gene expression and viral outgrowth.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- IL-17A reprograms intestinal epithelial cells to facilitate HIV-1 replication and outgrowth in CD4+ T cells.iScience · 2021Article
- The Role of Capsid in the Early Steps of HIV-1 Infection: New Insights into the Core of the Matter.Viruses · 2021Review
- Strategy, Progress, and Challenges of Drug Repurposing for Efficient Antiviral Discovery.Frontiers in pharmacology · 2021Review
- Filgotinib suppresses HIV-1-driven gene transcription by inhibiting HIV-1 splicing and T cell activation.The Journal of clinical investigation · 2020Article
- Hepatitis C Virus Influences HIV-1 Viral Splicing in Coinfected Patients.Journal of clinical medicine · 2020Article
- HIV-1 uncoats in the nucleus near sites of integration.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Cellular and molecular mechanisms of HIV-1 integration targeting.Cellular and molecular life sciences : CMLS · 2018Review
- Cardiac glycoside/aglycones inhibit HIV-1 gene expression by a mechanism requiring MEK1/2-ERK1/2 signaling.Scientific reports · 2018Article
Corrections and comments
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Authors and funding
12 authors at 5 institutions in 2 countries.
Funding
Abstract
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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.