title: Murine gammaherpesvirus 68 has evolved gamma interferon and stat1-repressible promoters for the lytic switch gene 50.
abstract: 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.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid Ave., Box 8118, St. Louis, MO 63110, USA.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Goodwin
authors.forename: Susan
authors.initials: S
authors.lastname: Canny
authors.forename: Ashley
authors.initials: A
authors.lastname: Steed
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
mesh_terms: D000818:Animals; D018142:Gammaherpesvirinae / Q000235:genetics*; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D050794:STAT1 Transcription Factor / Q000502:physiology*
chemical_list: D050794:STAT1 Transcription Factor; D007371:Interferon-gamma