Herpes simplex virus 2 ICP34.5 confers neurovirulence by regulating the type I interferon response

The γ34.5 gene of herpes simplex virus (HSV) 2 encodes ICP34.5, which enhances HSV-2 neurovirulence by an unknown mechanism. We found that an HSV-2 γ34.5-null mutant (γ34.5−/−) replicated less robustly than its rescue virus (γ34.5R) in wild-type mouse embryo fibroblasts (MEFs), and in cells primed with IFNβ. Increased eIF2α phosphorylation correlated with γ34.5−/− attenuation. However, γ34.5−/− achieved titers equivalent to γ34.5R in MEFs lacking the type I IFN receptor (IFNα/βR−/−) or lacking protein kinase R. γ34.5−/− also replicated poorly in the vaginal mucosa of wild-type mice, caused little genital inflammation, and spread to the nervous system at lower levels compared to γ34.5R. In IFNα/βR−/− mice, however, γ34.5−/− regained the capacity to replicate and cause disease equivalent to γ34.5R after intravaginal infection or direct inoculation into the central nervous system. Thus, the capacity of HSV-2 ICP34.5 to interdict the type I IFN response in vivo largely determines its neurovirulence.