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AIDS. 2015 Nov;29(17):2235-44. doi: 10.1097/QAD.0000000000000839.

Dose-responsive gene expression in suberoylanilide hydroxamic acid-treated resting CD4+ T cells.

Author information

  • 1aDepartment of Medicine bDepartment of Pathology, University of California San Diego, La Jolla cVeterans Affairs San Diego Healthcare System, San Diego, California, USA dFaculty of Medicine, University of Southampton, Southampton, Hants, UK eDepartments of Medicine, of Epidemiology, and of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Abstract

DESIGN:

Persistent latently infected CD4 T cells represent a major obstacle to HIV eradication. Histone deacetylase inhibitors (HDACis) are a proposed activation therapy. However, off-target effects on gene expression in host immune cells are poorly understood. We hypothesized that HDACi-modulated genes would be best identified with a dose-response analysis.

METHODS:

Resting primary CD4 T cells were treated with 0.34, 1, 3, or 10 μmol/l of the HDACi, suberoylanilide hydroxamic acid (SAHA), for 24 h and subjected to microarray gene expression analysis. Genes with dose-correlated expression were filtered to identify a subset with consistent up or downregulation at each SAHA dose. Histone modifications were characterized in six SAHA dose-responsive genes by chromatin immunoprecipitation (ChIP-RT-qPCR).

RESULTS:

A large number of genes were shown to be upregulated (N = 657) or downregulated (N = 725) by SAHA in a dose-responsive manner (FDR-corrected P-value ≤ 0.5, fold change ≥|2|). Several genes (e.g. CINNAL1, DPEP2, H1F0, IRGM, PHF15, and SELL) are potential in-vivo biomarkers of SAHA activity. SAHA dose-responsive genes included transcription factors, HIV restriction factors, histone methyltransferases, and host proteins that interact with HIV. Pathway analysis suggested net downregulation of T-cell activation with increasing SAHA dose. Histone acetylation was not correlated with host gene expression, but plausible alternative mechanisms for SAHA-modulated gene expression were identified.

CONCLUSION:

Numerous genes in CD4 T cells are modulated by SAHA in a dose-responsive manner, including genes that may negatively influence HIV activation from latency. Our study suggests that SAHA influences gene expression through a confluence of several mechanisms, including histone modification, and altered expression and activity of transcription factors.

PMID:
26258524
PMCID:
PMC4917679
DOI:
10.1097/QAD.0000000000000839
[PubMed - indexed for MEDLINE]
Free PMC Article
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