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

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

doi:10.1172/JCI137371

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

Yang-Hui Jimmy Yeh,¹ Katharine M. Jenike,² Rachela M. Calvi,³ Jennifer Chiarella,³ Rebecca Hoh,⁴ Steven G. Deeks,⁴ and Ya-Chi Ho¹

Published June 23, 2020 - More info

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Abstract

Despite effective antiretroviral therapy, HIV-1-nfected cells continue to produce viral antigens and induce chronic immune exhaustion. We propose to identify HIV-1-suppressing agents which can inhibit HIV-1 reactivation and reduce HIV-1-induced immune activation. Using a novel dual reporter system and a high-throughput drug screen, we identified FDA-approved drugs which 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 a new function of a JAK inhibitor filgotinib which 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 systemic understanding of cellular targets required for HIV-1 reactivation and drug candidates that may reduce HIV-1-related immune activation.

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

Yang-Hui Jimmy Yeh,¹ Katharine M. Jenike,² Rachela M. Calvi,³ Jennifer Chiarella,³ Rebecca Hoh,⁴ Steven G. Deeks,⁴ and Ya-Chi Ho¹

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

Yang-Hui Jimmy Yeh,1 Katharine M. Jenike,2 Rachela M. Calvi,3 Jennifer Chiarella,3 Rebecca Hoh,4 Steven G. Deeks,4 and Ya-Chi Ho1

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Yang-Hui Jimmy Yeh,¹ Katharine M. Jenike,² Rachela M. Calvi,³ Jennifer Chiarella,³ Rebecca Hoh,⁴ Steven G. Deeks,⁴ and Ya-Chi Ho¹