Submitted March 28, 2006
Accepted July 21, 2006
Histone deacetylase inhibitors increase virus gene expression but decrease CD8+ cell anti-viral function in HTLV-I infection
Angelina Jane Mosley, Kiran N Meekings, Corinna McCarthy, Dawn Shepherd, Vincenzo Cerundolo, Ralph Mazitschek, Yuetsu Tanaka, Graham P Taylor, and Charles R Bangham*
Imperial College of Science, Technology and Medicine
Weatherall Institute of Molecular Medicine, University of Oxford
Howard Hughes Medical Institute
Faculty of Medicine, University of Ryukyus
* Corresponding author; email: c.bangham{at}imperial.ac.uk.
The dynamics of Human T-Lymphotropic Virus Type-1 (HTLV-1) provirus expression in vivo are unknown. There is much evidence to suggest that HTLV-1 gene expression is restricted: this restricted gene expression may contribute to HTLV-1 persistence by limiting the ability of the HTLV-1-specific CD8+ cell immune response to clear infected cells. In this study we tested the hypothesis that de-repression of HTLV-1 gene expression would allow an increase in CD8+ cell-mediated lysis of HTLV-1-infected cells. Using histone deacetylase enzyme inhibitors (HDI) to hyperacetylate histones and increase HTLV-1 gene expression we found that HDI doubled Tax expression in naturally infected lymphocytes after overnight culture. However, the rate of CD8+ cell-mediated lysis of Tax expressing cells ex vivo was halved. HDI appeared to inhibit the CD8+ cell-mediated lytic process itself, indicating a role for the microtubule-associated HDAC6 enzyme. These observations indicate that HDI may reduce the efficiency of CTL surveillance of HTLV-1 in vivo. Although the impact of HDI on HTLV-1 proviral load in vivo cannot be accurately predicted because of the widespread effects of these drugs on cellular processes, we therefore recommend caution in the use of HDI in non-malignant cases of HTLV-1 infection.
