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

Area of Science:

• Immunology
• Molecular Biology
• Virology

Background:

• Persistent latently infected CD4 T cells are a major barrier to HIV eradication.
• Histone deacetylase inhibitors (HDACis) are investigated for HIV activation therapy.
• Understanding off-target gene expression effects of HDACis in immune cells is crucial.

Purpose of the Study:

• To identify genes modulated by HDACi treatment in a dose-dependent manner.
• To investigate the impact of suberoylanilide hydroxamic acid (SAHA) on CD4 T cell gene expression.
• To explore potential biomarkers and mechanisms of SAHA's action.

Main Methods:

• Primary CD4 T cells were treated with varying doses of SAHA (0.34–10 μmol/l).
• Microarray analysis was used to assess gene expression changes.
• Chromatin immunoprecipitation (ChIP-RT-qPCR) was employed to characterize histone modifications.

Main Results:

• SAHA significantly upregulated 657 genes and downregulated 725 genes in a dose-responsive manner.
• Identified potential in-vivo biomarkers of SAHA activity (e.g., CINNAL1, DPEP2, H1F0).
• Pathway analysis indicated a net downregulation of T-cell activation with increasing SAHA doses.

Conclusions:

• SAHA dose-responsively modulates numerous genes in CD4 T cells, including those affecting HIV latency.
• SAHA influences gene expression via multiple mechanisms, including histone modification and transcription factor activity.
• Findings provide insights into HDACi-based HIV eradication strategies.