Transcriptional and methylation outcomes of didehydro-cortistatin A use in HIV-1-infected CD4 + T cells.

Autor:	Mori LP; The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, FL, USA.; Department of Immunology and Microbiology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA., Corley MJ; Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, New York, NY, USA., McAuley AT; Department of Immunology and Microbiology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA., Pang A; Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, New York, NY, USA., Venables T; Department of Immunology and Microbiology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA., Ndhlovu LC; Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, New York, NY, USA., Pipkin ME; The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, FL, USA.; Department of Immunology and Microbiology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA., Valente ST; The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, FL, USA svalente@ufl.edu.; Department of Immunology and Microbiology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA.
Jazyk:	angličtina
Zdroj:	Life science alliance [Life Sci Alliance] 2024 Aug 01; Vol. 7 (10). Date of Electronic Publication: 2024 Aug 01 (Print Publication: 2024).
DOI:	10.26508/lsa.202402653
Abstrakt:	Ongoing viral transcription from the reservoir of HIV-1 infected long-lived memory CD4 + T cells presents a barrier to cure and associates with poorer health outcomes for people living with HIV, including chronic immune activation and inflammation. We previously reported that didehydro-cortistatin A (dCA), an HIV-1 Tat inhibitor, blocks HIV-1 transcription. Here, we examine the impact of dCA on host immune CD4 + T-cell transcriptional and epigenetic states. We performed a comprehensive analysis of genome-wide transcriptomic and DNA methylation profiles upon long-term dCA treatment of primary human memory CD4 + T cells. dCA prompted specific transcriptional and DNA methylation changes in cell cycle, histone, interferon-response, and T-cell lineage transcription factor genes, through inhibition of both HIV-1 and Mediator kinases. These alterations establish a tolerogenic Treg/Th2 phenotype, reducing viral gene expression and mitigating inflammation in primary CD4 + T cells during HIV-1 infection. In addition, dCA suppresses the expression of lineage-defining transcription factors for Th17 and Th1 cells, critical HIV-1 targets, and reservoirs. dCA's benefits thus extend beyond viral transcription inhibition, modulating the immune cell landscape to limit HIV-1 acquisition and inflammatory environment linked to HIV infection. (© 2024 Mori et al.)
Databáze:	MEDLINE
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