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- Title
Filgotinib suppresses HIV-1-driven gene transcription by inhibiting HIV-1 splicing and T cell activation.
- Authors
Yang-Hui Jimm Yeh; Jenike, Katharine M.; Calvi, Rachela M.; Chiarella, Jennifer; Hoh, Rebecca; Deeks, Steven G.; Ya-Chi Ho; Yeh, Yang-Hui Jimmy; Ho, Ya-Chi
- Abstract
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.
- Subjects
UNITED States. Food &; Drug Administration; T cells; RNA splicing; VIRAL antigens; GENE expression; INTRONS; HIV infections; PYRIDINE; RESEARCH; HETEROCYCLIC compounds; RESEARCH methodology; IMMUNOLOGY technique; RNA; EVALUATION research; MEDICAL cooperation; COMPARATIVE studies; RESEARCH funding; HIV
- Publication
Journal of Clinical Investigation, 2020, Vol 130, Issue 9, p4969
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI137371