Regulation of the lytic switch gene 50 in murine gammaherpesvirus 68

Gammaherpesviruses are important oncogenic pathogens that can transit between lytic and latent life cycles. In murine gammaherpesvirus 68 (gammaHV68), the essential lytic switch gene 50 controls the interchange between lytic and latent gene expression programs. Silencing gene 50 transcription ensures that genes in the lytic cascade are not expressed, thus allowing for the latent gene expression program. Negative regulators of gene 50 expression remain largely undefined.;Secreted cytokines and hormones regulate viral gene expression with important consequences for viral replication and pathogenesis. We report here that the cytokine interferon-gamma (IFN-gamma) inhibits lytic replication of gammaHV68, decreases gene 50 transcript levels, and suppresses activity of the two known gene 50 promoters. This is the first example of an inflammatory cytokine directly regulating the promoters for the gammaHV68 lytic switch gene.;Furthermore, we report cell type-specific silencing of the gammaHV68 lytic cycle that is mediated by histone deacetylases (HDACs). HDAC inhibition relieves gammaHV68 silencing by inducing the lytic switch gene 50 promoter. Moreover, we have identified a specific role for HDAC3, HDAC4, and the nuclear receptor corepressor (NCoR) in silencing of gammaHV68. The vitamin A derivative, retinoic acid, is a known ligand for the NCoR complex and it derepresses gene 50 expression and enhances gammaHV68 lytic replication. Moreover HDAC3, HDAC4 and NCoR bind directly to the gene 50 promoter in a retinoic acid responsive manner. We provide the first example of NCoR-mediated, HDAC-dependent regulation of viral gene expression.