title: Herpes simplex virus 2 ICP34.5 confers neurovirulence by regulating the type I interferon response.
abstract: 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.
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, 1100 South Grand Boulevard, St. Louis, MO 63104, USA.
authors.forename: Katie L
authors.initials: KL
authors.lastname: Davis
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, 1100 South Grand Boulevard, St. Louis, MO 63104, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Korom
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, 1100 South Grand Boulevard, St. Louis, MO 63104, USA. Electronic address: morrisla@slu.edu.
authors.forename: Lynda A
authors.initials: LA
authors.lastname: Morrison
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D017353:Gene Deletion; D015967:Gene Expression Regulation, Viral / Q000502:physiology*; D018258:Herpesvirus 2, Human / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
chemical_list: C540071:ICP34.5 protein, human herpesvirus-2; D014764:Viral Proteins; D053633:Receptor, Interferon alpha-beta
keywords: CNS; Central nervous system; HSV-2; Herpes simplex virus; IFN; Interferon; Vaginal