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

The 734.5 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 gamma 34.5-null mutant (gamma 34.5(-/-)) replicated less robustly than its rescue virus (gamma 34.5R) in wild-type mouse embryo fibroblasts (MEFs), and in cells primed with IFN beta. Increased eIF2 alpha phosphorylation correlated with gamma 34.5(-/-) attenuation. However, gamma 34.5(-/-) achieved titers equivalent to gamma 34.5R in MEFs lacking the type I IFN receptor (IFN alpha/beta R-/-) or lacking protein kinase R. gamma 34.5(-/-) 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 gamma 34.5R. In IFN alpha/beta R-/- mice, however, gamma 34.5(-/-) regained the capacity to replicate and cause disease equivalent to gamma 34.5R 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. (C) 2014 Elsevier Inc. All rights reserved.