Vaccinia virus blocks gamma interferon signal transduction: Viral VH1 phosphatase reverses Stat1 activation

We have analyzed the effects of vaccinia virus (VV) on gamma interferon (IF N-gamma) signal transduction, Infection of cells with VV 1 to 2 h prior to treatment with IFN-gamma inhibits phosphorylation and nuclear translocation of Stat1 and consequently blocks accumulation of mRNAs normally induced by IFN-gamma, While phosphorylation of other proteins in the IFN-gamma pathwa y was not affected, activation of Stat1 by other ligand-receptor systems wa s also blocked by VV, This block of Stat1 activation was dose dependent, an d although viral protein synthesis was not required, entry and uncoating of viral cores appear to be needed to block the accumulation of phosphorylate d Stat1, These results suggest that a virion component is responsible for t he effect. VV virions contain a phosphatase (VH1) that is sensitive to the phosphatase inhibitor Na3VO4 but not to okadaic acid. Addition of Na3VO4 bu t not okadaic acid restored normal Stat1 phosphorylation levels in VV-infec ted cells. Moreover, virions containing reduced levels of VH1 were unable t o block the IFN-gamma signaling pathway. In vitro studies show that the pho sphatase can bind and dephosphorylate Stat1, indicating that this transcrip tion factor can be a substrate for VH1, Our results reveal a novel mechanis m by which VV interferes with the onset of host immune responses by blockin g the IFN-gamma signal cascade through the dephosphorylating activity of th e viral phosphatase VH1.