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Filgotinib suppresses HIV-1–driven gene transcription by inhibiting HIV-1 splicing and T cell activation
Yang-Hui Jimmy Yeh, … , Steven G. Deeks, Ya-Chi Ho
Yang-Hui Jimmy Yeh, … , Steven G. Deeks, Ya-Chi Ho
Published June 23, 2020
Citation Information: J Clin Invest. 2020;130(9):4969-4984. https://doi.org/10.1172/JCI137371.
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Research Article AIDS/HIV Article has an altmetric score of 71

Filgotinib suppresses HIV-1–driven gene transcription by inhibiting HIV-1 splicing and T cell activation

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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.

Authors

Yang-Hui Jimmy Yeh, Katharine M. Jenike, Rachela M. Calvi, Jennifer Chiarella, Rebecca Hoh, Steven G. Deeks, Ya-Chi Ho

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Figure 6

Filgotinib induces intron retention in RNA processing–related genes in both HIV-1–infected Jurkat clone 8B10 and CD4+ T cells from virally suppressed HIV-1–infected individuals.

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Filgotinib induces intron retention in RNA processing–related genes in b...
(A) The number of intron-retained genes identified by IRFinder (77) in CD4+ T cells treated with HIV-1–suppressing agents using samples described in Figure 5. CD4+ T cells were obtained from 3 virally suppressed HIV-1–infected individuals (participants 1021, 1024, and 1025) treated with 10 μM HIV-1–suppressing agents for 24 hours in the presence of ART (1 μM tenofovir and 10 μM enfuvirtide). Intron-retained regions with significantly increased ratio (P < 0.05, unequal-variances t test) are reported. (B) Disease and biological function pathway analysis of intron-retained genes using IPA in CD4+ T cells from 3 virally suppressed HIV-1–infected individuals treated with filgotinib. (C–F) Integrative genome viewer plots of representative RNA landscape of HNRNPH1 and DDX41 demonstrate intron retention in these genes (blue arrowheads) in HIV-1–dsGFP Jurkat clone 8B10 (C and E) and in CD4+ T cells from virally suppressed HIV-1–infected individuals (D and F). (G) Western blot of intron-retained genes HNRNPH1 and DDX41 in HIV-1–infected Jurkat 8B10 cells treated with HIV-1–suppressing agents. DM, DMSO; Fi, filgotinib; Ru, ruxolitinib; Sp, spironolactone; MA, mycophenolic acid.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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