Objectives: A family of histone deacetylases (HDACs) mediates chromatin remodeling, and repression of gene expression. Deacetylation of histones within the HIV-1 long terminal repeat (LTR) by HDACs plays a key role in the maintenance of latency, whereas acetylation of histones about the LTR is linked to proviral expression and escape of HIV from latency. Global HDAC inhibition may adversely affect host gene expression, leading to cellular toxicities. Potent inhibitors selective for HDACs that maintain LTR repression could be ideal antilatency therapeutics.
Methods: We investigated the ability of selective HDAC inhibitors to de-repress the HIV-1 LTR in both a cell line model of latency and in resting CD4+ T cells isolated from patients who were aviremic on antiretroviral therapy (ART).
Results: We found that inhibition of class I HDACs increased acetylation of histones at the LTR, but that LTR chromatin was unaffected by class II HDAC inhibitors. In a latently infected cell line, inhibitors selective for class I HDACs were more efficient activators of the LTR than inhibitors that target class II HDACs. Class I HDAC inhibitors were strikingly efficient inducers of virus outgrowth from resting CD4+ T cells of aviremic patients, whereas HIV was rarely recovered from patient's cells exposed to class II HDAC inhibitors.
Conclusions: Further development of selective HDAC inhibitors as part of a clinical strategy to target persistent HIV infection is warranted.
aDepartment of Medicine, USA
bDepartment of Microbiology and Immunology, USA
cDepartment of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
dDepartment of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania, USA.
Received 5 January, 2009
Revised 21 May, 2009
Accepted 29 May, 2009
Correspondence to David M. Margolis, University of North Carolina at Chapel Hill, 3302 Michael Hooker Research Ctr., CB#7435 Chapel Hill, NC 27599-7435, USA. Tel: +1 919 966 6388; fax: +1 919 966 0584; e-mail: email@example.com