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Filgotinib suppresses HIV-1-driven gene transcription by inhibiting HIV-1 splicing and T cell activation.
Yeh, Yang-Hui Jimmy; Jenike, Katharine M; Calvi, Rachela M; Chiarella, Jennifer; Hoh, Rebecca; Deeks, Steven G; Ho, Ya-Chi.
Affiliation
  • Yeh YJ; Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut, USA.
  • Jenike KM; Human Genetics PhD Program, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Calvi RM; Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA.
  • Chiarella J; Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA.
  • Hoh R; Department of Medicine, UCSF, San Francisco, California, USA.
  • Deeks SG; Department of Medicine, UCSF, San Francisco, California, USA.
  • Ho YC; Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut, USA.
J Clin Invest ; 130(9): 4969-4984, 2020 09 01.
Article in En | MEDLINE | ID: mdl-32573496
Despite effective antiretroviral therapy, HIV-1-infected cells continue to produce viral antigens and induce chronic immune exhaustion. We propose to identify HIV-1-suppressing agents that can inhibit HIV-1 reactivation and reduce HIV-1-induced immune activation. Using a newly developed dual-reporter system and a high-throughput drug screen, we identified FDA-approved drugs that can suppress HIV-1 reactivation in both cell line models and CD4+ T cells from virally suppressed HIV-1-infected individuals. We identified 11 cellular pathways required for HIV-1 reactivation as druggable targets. Using differential expression analysis, gene set enrichment analysis, and exon-intron landscape analysis, we examined the impact of drug treatment on the cellular environment at a genome-wide level. We identified what we believe to be a new function of a JAK inhibitor, filgotinib, that suppresses HIV-1 splicing. First, filgotinib preferentially suppresses spliced HIV-1 RNA transcription. Second, filgotinib suppresses HIV-1-driven aberrant cancer-related gene expression at the integration site. Third, we found that filgotinib suppresses HIV-1 transcription by inhibiting T cell activation and by modulating RNA splicing. Finally, we found that filgotinib treatment reduces the proliferation of HIV-1-infected cells. Overall, the combination of a drug screen and transcriptome analysis provides systematic understanding of cellular targets required for HIV-1 reactivation and drug candidates that may reduce HIV-1-related immune activation.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyridines / Transcription, Genetic / Triazoles / Lymphocyte Activation / CD4-Positive T-Lymphocytes / HIV Infections / RNA Splicing / HIV-1 Limits: Humans Language: En Journal: J Clin Invest Year: 2020 Type: Article Affiliation country: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyridines / Transcription, Genetic / Triazoles / Lymphocyte Activation / CD4-Positive T-Lymphocytes / HIV Infections / RNA Splicing / HIV-1 Limits: Humans Language: En Journal: J Clin Invest Year: 2020 Type: Article Affiliation country: United States