Val193 and Phe195 of the γ134.5 protein of herpes simplex virus 1 are required for viral resistance to interferon-α/β

Herpes simplex viruses (HSV) are resistant to the antiviral action of interferon. However, the underlying mechanisms are not well understood. In this report, we show that unlike that of wild-type HSV-1, replication of the gamma (1)34.5 null mutants was significantly inhibited by exogenous interferon-alpha in cells devoid of interferon-alpha/beta genes. Using a series of gamma (1)34.5 deletion mutants, the domain required for interferon resistance was mapped to the region containing amino acids 146 to 263 in the gamma (1)34.5 protein. Interestingly, Val(193)Glu and Phe(195)Leu substitutions in the protein phosphatase 1 interacting motif of the gamma (1)34.5 protein rendered HSV-1 sensitive to interferon-alpha. Furthermore, gamma (1)34.5 null mutants were sensitive to interferon-alpha/beta in PKR+/+ but not in PKR-/- mouse embryo fibroblasts. These findings provide evidence that the gamma (1)34.5 protein contributes to HSV-1 resistance to interferon-alpha/beta by inhibiting PKR function. (C) 2001 Academic Press.