1. Filgotinib suppresses HIV-1-driven gene transcription by inhibiting HIV-1 splicing and T cell activation
- Author
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Rebecca Hoh, Jennifer Chiarella, Katharine M. Jenike, Yang-Hui Jimmy Yeh, Rachela M. Calvi, Ya Chi Ho, and Steven G. Deeks
- Subjects
0301 basic medicine ,CD4-Positive T-Lymphocytes ,Transcription, Genetic ,Pyridines ,HIV Infections ,Lymphocyte Activation ,Medical and Health Sciences ,Transcriptome ,Jurkat Cells ,0302 clinical medicine ,Transcription (biology) ,Gene expression ,Drug screens ,Cancer ,virus diseases ,General Medicine ,Cell biology ,medicine.anatomical_structure ,Infectious Diseases ,5.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,6.1 Pharmaceuticals ,RNA splicing ,HIV/AIDS ,Development of treatments and therapeutic interventions ,Infection ,Transcription ,Research Article ,Biotechnology ,Filgotinib ,T cell ,RNA Splicing ,Immunology ,T cells ,Therapeutics ,Biology ,AIDS/HIV ,03 medical and health sciences ,Immune system ,Genetic ,medicine ,Genetics ,Humans ,Expression profiling ,Human Genome ,Evaluation of treatments and therapeutic interventions ,Triazoles ,Gene expression profiling ,030104 developmental biology ,HIV-1 - 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.
- Published
- 2020