Antagonism of the protein kinase R pathway by the guinea pig cytomegalovirus US22-family gene gp145

Viral double-stranded RNA (dsRNA) activates protein kinase R (PKR), which phosphorylates eIF2α and inhibits translation. In response, viruses have evolved various strategies to evade the antiviral impact of PKR. We investigated whether guinea pig cytomegalovirus (GPCMV), a useful model of congenital CMV infection, encodes a gene that interferes with the PKR pathway. Using a proteomic screen, we identified several GPCMV dsRNA-binding proteins, among which only gp145 rescued replication of a vaccinia virus mutant that lacks E3L. gp145 also reversed the inhibitory effects of PKR on expression of a cotransfected reporter gene. Mapping studies demonstrated that the gp145 dsRNA-binding domain has homology to the PKR antagonists of other CMVs. However, dsRNA-binding by gp145 is not sufficient for it to block PKR. gp145 differs from the PKR antagonists of murine CMV in that it functions alone and from those encoded by human CMV in functioning in cells from both primates and rodents.