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Citations to this article

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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Total citations by year

Year: 2024 2023 2022 2021 2020 Total
Citations: 11 2 5 9 1 28
Citation information
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Citations to this article (28)

Title and authors Publication Year
Machine Learning Bolsters Evidence That D1, Nef, and Tat Influence HIV Reservoir Dynamics
Cannon L, Fehrman S, Pinzone M, Weissman S, O'Doherty U
Pathogens and Immunity 2024
Immunosuppressants exert antiviral effects against influenza A(H1N1)pdm09 virus via inhibition of nucleic acid synthesis, mRNA splicing, and protein stability.
Wang X, Pu F, Yang X, Feng X, Zhang J, Duan K, Nian X, Ma Z, Ma XX, Yang XM
Virulence 2024
Persistent HIV-1 transcription during ART: time to reassess its significance?
Fombellida-Lopez C, Berkhout B, Darcis G, Pasternak AO
Current Opinion in HIV and AIDS 2024
Targeting Viral Transcription for HIV Cure Strategies.
Izquierdo-Pujol J, Puertas MC, Martinez-Picado J, Morón-López S
Microorganisms 2024
Transcription of HIV-1 at sites of intact latent provirus integration
Teixeira AR, Bittar C, Silva Santos GS, Oliveira TY, Huang AS, Linden N, Ferreira IA, Murdza T, Muecksch F, Jones RB, Caskey M, Jankovic M, Nussenzweig MC
2024
Post-Transcriptional HIV-1 Latency: A Promising Target for Therapy?
Kobayashi-Ishihara M, Tsunetsugu-Yokota Y
Viruses 2024
Effects of an indole derivative on cell proliferation, transfection, and alternative splicing in production of lentiviral vectors by transient co-transfection
Mier NC, Roper DK
PloS one 2024
Mechanisms and efficacy of small molecule “latency promoting agents” to inhibit HIV reactivation in cells from people with HIV
Julie Janssens, Peggy Kim, Sun Jin Kim, Adam Wedrychowski, Gayatri Kadiyala, Peter Hunt, Steven Deeks, Joseph Wong, Steven Yukl
JCI Insight 2024
Transcription of HIV-1 at sites of intact latent provirus integration.
Teixeira AR, Bittar C, Silva Santos GS, Oliveira TY, Huang AS, Linden N, Ferreira IATM, Murdza T, Muecksch F, Jones RB, Caskey M, Jankovic M, Nussenzweig MC
The Journal of experimental medicine 2024
Silencing the transcriptionally active HIV reservoir to improve treatment outcomes.
Prigann J, Tavora R, Furler O'Brien RL, Schulze-Gahmen U, Boehm D, Roan NR, Nixon DF, Ndhlovu LC, Valente S, Ott M
Nature microbiology 2024
Exploiting the Achilles’ Heel of Viral RNA Processing to Develop Novel Antivirals
Zahedi Amiri A, Ahmed C, Dahal S, Grosso F, Leng H, Stoilov P, Mangos M, Toutant J, Shkreta L, Attisano L, Chabot B, Brown M, Huesca M, Cochrane A
Viruses 2024
Integration site–dependent HIV-1 promoter activity shapes host chromatin conformation
Collora JA, Ho YC
Genome research 2023
Single-cell epigenetic, transcriptional, and protein profiling of latent and active HIV-1 reservoir revealed that IKZF3 promotes HIV-1 persistence
Wei Y, Davenport TC, Collora JA, Ma HK, Pinto-Santini D, Lama J, Alfaro R, Duerr AC, Ho YC
Immunity 2023
DEAD-ly Affairs: The Roles of DEAD-Box Proteins on HIV-1 Viral RNA Metabolism
Rao S, Mahmoudi T
Frontiers in Cell and Developmental Biology 2022
Single-cell multiomics reveals persistence of HIV-1 in expanded cytotoxic T cell clones
Collora JA, Liu R, Pinto-Santini D, Ravindra N, Ganoza C, Lama JR, Alfaro R, Chiarella J, Spudich S, Mounzer K, Tebas P, Montaner LJ, van Dijk D, Duerr A, Ho YC
Immunity 2022
Inhibition of a Chromatin and Transcription Modulator, SLTM, Increases HIV-1 Reactivation Identified by a CRISPR Inhibition Screen.
Pedersen SF, Collora JA, Kim RN, Yang K, Razmi A, Catalano AA, Yeh YJ, Mounzer K, Tebas P, Montaner LJ, Ho YC
Journal of virology 2022
HibeRNAtion: HIV-1 RNA Metabolism and Viral Latency.
Crespo R, Rao S, Mahmoudi T
Frontiers in Cellular and Infection Microbiology 2022
Opposing roles of CLK SR kinases in controlling HIV-1 gene expression and latency.
Dahal S, Clayton K, Been T, Fernet-Brochu R, Ocando AV, Balachandran A, Poirier M, Maldonado RK, Shkreta L, Boligan KF, Guvenc F, Rahman F, Branch D, Bell B, Chabot B, Gray-Owen SD, Parent LJ, Cochrane A
Retrovirology 2022
Cell-Associated HIV-1 Unspliced-to-Multiply-Spliced RNA Ratio at 12 Weeks of ART Predicts Immune Reconstitution on Therapy
M Scherpenisse, NA Kootstra, M Bakker, B Berkhout, AO Pasternak, TE Smithgall
mBio 2021
Shock-and-kill versus block-and-lock: Targeting the fluctuating and heterogeneous HIV-1 gene expression
YH Yeh, YC Ho
Proceedings of the National Academy of Sciences 2021
The Splice of Life: Does RNA Processing Have a Role in HIV-1 Persistence?
AO Pasternak, B Berkhout
Viruses 2021
Research priorities for an HIV cure: International AIDS Society Global Scientific Strategy 2021
SG Deeks, N Archin, P Cannon, S Collins, RB Jones, MA de Jong, O Lambotte, R Lamplough, T Ndungu, J Sugarman, CT Tiemessen, L Vandekerckhove, SR Lewin, S Deeks, S Lewin, M de Jong, Z Ndhlovu, N Chomont, Z Brumme, K Deng, L Jasenosky, R Jefferys, A Orta-Resendiz, F Mardarelli, M Nijhuis, K Bar, B Howell, A Schneider, G Turk, R Nabatanzi, J Blankson, JV Garcia, M Paiardini, J van Lunzen, C Antoniadi, FH Côrtes, S Valente, OS Søgaard, RS Diaz, M Ott, R Dunham, S Schwarze, SP Patrigeon, J Nabukenya, M Caskey, B Mothe, FS Wang, S Fidler, D SenGupta, S Dressler, M Matoga, HP Kiem, P Tebas, C Kityo, B Dropulic, M Louella, KT Das, D Persaud, A Chahroudi, K Luzuriaga, T Puthanakit, J Safrit, G Masheto, K Dubé, J Power, J Salzwedel, U Likhitwonnawut, J Taylor, OL Nuh, K Dong, EN Kankaka
Nature Medicine 2021
The Clonal Expansion Dynamics of the HIV-1 Reservoir: Mechanisms of Integration Site-Dependent Proliferation and HIV-1 Persistence
YH Yeh, K Yang, A Razmi, YC Ho
Viruses 2021
The JAK/STAT signaling pathway: from bench to clinic
X Hu, J li, M Fu, X Zhao, W Wang
Signal Transduction and Targeted Therapy 2021
A New Small-Molecule Compound, Q308, Silences Latent HIV-1 Provirus by Suppressing Tat- and FACT-Mediated Transcription
C Zhou, Y Huang, Y Li, T Liang, T Zheng, P Chen, Z Wu, F Lai, S Liu, , L Li
Antimicrobial agents and chemotherapy 2021
The Role of L-Selectin in HIV Infection
J Segura, B He, J Ireland, Z Zou, T Shen, G Roth, PD Sun
Frontiers in microbiology 2021
JAK-STAT Pathway: A Novel Target to Tackle Viral Infections
I Ezeonwumelu, E Garcia-Vidal, E Ballana
Viruses 2021
The single-cell landscape of immunological responses of CD4+ T cells in HIV versus severe acute respiratory syndrome coronavirus 2
JA Collora, R Liu, K Albrecht, YC Ho
Current Opinion in HIV and AIDS 2020

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