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Previous studies identified a role for latent herpesvirus infection in cross-protection against infection and exacerbation of chronic inflammatory diseases. Here, we identified more than 500 genes differentially expressed in spleens, livers, or brains of mice latently infected with gammaherpesvirus 68 and found that distinct sets of genes linked to different pathways were altered in the spleen compared to those in the liver. Several of the most differentially expressed latency-specific genes (e.g., the gamma interferon [IFN-γ], Cxcl9, and Ccl5 genes) are associated with known latency-specific phenotypes. Chronic herpesvirus infection, therefore, significantly alters the transcriptional status of host organs. We speculate that such changes may influence host physiology, the status of the immune system, and disease susceptibility.

Gammaherpesviruses are important oncogenic pathogens that transit between lytic and latent life cycles. Silencing the lytic gene expression program enables the establishment of latency and a lifelong chronic infection of the host. In murine gammaherpesvirus 68 (MHV68, γHV68), essential lytic switch gene 50 controls the interchange between lytic and latent gene expression programs. However, negative regulators of gene 50 expression remain largely undefined. We report that the MHV68 lytic cycle is silenced in infected macrophages but not fibroblasts and that histone deacetylases (HDACs) mediate silencing. The HDAC inhibitor trichostatin A (TSA) acts on the gene 50 promoter to induce lytic replication of MHV68. HDAC3, HDAC4, and the nuclear receptor corepressor (NCoR) are required for efficient silencing of gene 50 expression. NCoR is critical for transcriptional repression of cellular genes by unliganded nuclear receptors. Retinoic acid, a known ligand for the NCoR complex, derepresses gene 50 expression and enhances MHV68 lytic replication. Moreover, HDAC3, HDAC4, and NCoR act on the gene 50 promoter and are recruited to this promoter in a retinoic acid-responsive manner. We provide the first example of NCoR-mediated, HDAC-dependent regulation of viral gene expression.

Cytokines regulate viral gene expression with important consequences for viral replication and pathogenesis. Gamma interferon (IFN-gamma) is a key regulator of chronic murine gammaherpesvirus 68 (gammaHV68) infection and a potent inhibitor of gammaHV68 reactivation from latency. Macrophages are the cell type that is responsive to the IFN-gamma-mediated control of gammaHV68 reactivation; however, the molecular mechanism of this IFN-gamma action is undefined. Here we report that IFN-gamma inhibits lytic replication of gammaHV68 in primary bone marrow-derived macrophages and decreases transcript levels for the essential lytic switch gene 50. Interestingly, IFN-gamma suppresses the activity of the two known gene 50 promoters, demonstrating that an inflammatory cytokine can directly regulate the promoters for the gammaHV68 lytic switch gene. Stat1, but not IFN-alpha/beta signaling, is required for IFN-gamma action. Moreover, Stat1 deficiency increases basal gammaHV68 replication, gene 50 expression, and promoter activity. Together, these data identify IFN-gamma and Stat1 as being negative regulators of the gammaHV68 lytic cycle and raise the possibility that gammaHV68 maintains IFN-gamma/Stat1-responsive gene 50 promoters to facilitate cell-extrinsic control over the interchange between the lytic and latent cycles.