Evidence suggests that herpes simplex virus type 1 (HSV-1) DNA associates with histones during the latent infection. In various models of gene expression, silencing of genes has been shown to be regulated by histone deacetylases (HDAC) that alter the conformation of the nucleosomal core histone tails. Objectives: To determine the possible role of HDACs in gene silencing during HSV latency, we investigated HDAC-dependent processes in our in vitro model for quiescent HSV-1 infection that allows study of cryptic HSV DNA in neuronal cells. Methods: Quiescently infected (QIF)-PC12 cultures were established with strain 17+ and treated with sodium butyrate (NaB), a histone deacetylase inhibitor, on day 17 post infection. Results: This inducer (50 mM) reactivated HSV-1 in 100% (24/24) of QIF cultures compared with 17% (4/23) of mock-induced cultures (p < 0.05). Since NaB inhibits histone deacetylases, but also has other activities, QIF-PC12 cells were subsequently treated with trichostatin A (TSA), a specific inhibitor of histone deacetylase. Treatment with TSA (400 ng/ml) induced virus production in 70.8% (17/24) of QIF cultures, whereas mock treatment yielded virus in only 4.3% (1/23) (p < 0.05). The response to NaB and TSA occurred in a dose dependent manner and was similar to that of heat stress and forskolin treatment. Similar results were seen using a recombinant HSV-1 (984) that expresses enhanced green fluorescent protein in an immediate early viral gene. This line of investigation allowed us to examine the percentage of cells that initiate activation and support productive infection. Conclusions: These results suggest that inhibition of histone deacetylation is a potent method for activating genes required for HSV activation and may shed light on the state of the viral DNA in quiescence. This study was supported by the University of Kentucky Medical Center Grant fund.

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