Histone deacetylase inhibitors increase virus gene expression but decrease CD8+ cell antiviral function in HTLV-1 infection.
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 derepression of HTLV-1 gene expression would allow an increase in CD8(+) cell-mediated lysis of HTLV-1-infected cells. Using histone deacetylase enzyme inhibitors (HDIs) to hyperacetylate histones and increase HTLV-1 gene expression, we found that HDIs 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. HDIs appeared to inhibit the CD8(+) cell-mediated lytic process itself, indicating a role for the microtubule-associated HDAC6 enzyme. These observations indicate that HDIs may reduce the efficiency of cytotoxic T-cell (CTL) surveillance of HTLV-1 in vivo. The impact of HDIs 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 HDIs in nonmalignant cases of HTLV-1 infection.
Mosley
Angelina Jane
AJ
Department of Immunology, Wright Fleming Institute, Imperial College London, Norfolk Place, London, United Kingdom.
Meekings
Kiran N
KN
McCarthy
Corinna
C
Shepherd
Dawn
D
Cerundolo
Vincenzo
V
Mazitschek
Ralph
R
Tanaka
Yuetsu
Y
Taylor
Graham P
GP
Bangham
Charles R
CR
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D015331:Cohort Studies; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000187:drug effects* / Q000276:immunology; D016356:Gene Products, tax / Q000235:genetics / Q000276:immunology; D015490:HTLV-I Infections / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000276:immunology; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D008297:Male; D011533:Proviruses / Q000235:genetics / Q000276:immunology
D004791:Enzyme Inhibitors; D016356:Gene Products, tax; D056572:Histone Deacetylase Inhibitors; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases