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 γ₁34.5 null mutants was significantly inhibited by exogenous interferon-α in cells devoid of interferon-α/β genes. Using a series of γ₁34.5 deletion mutants, the domain required for interferon resistance was mapped to the region containing amino acids 146 to 263 in the γ₁34.5 protein. Interestingly, Val¹⁹³Glu and Phe¹⁹⁵Leu substitutions in the protein phosphatase 1 interacting motif of the γ₁34.5 protein rendered HSV-1 sensitive to interferon-α. Furthermore, γ₁34.5 null mutants were sensitive to interferon-α/β in PKR+/+ but not in PKR-/- mouse embryo fibroblasts. These findings provide evidence that the γ₁34.5 protein contributes to HSV-1 resistance to interferon-α/β by inhibiting PKR function.