title: Type I IFN response to Papiine herpesvirus 2 (Herpesvirus papio 2; HVP2) determines neuropathogenicity in mice.
abstract: Isolates of baboon alpha-herpesvirus Papiine herpesvirus 2 (HVP2) exhibit one of two distinct phenotypes in mice: extremely neurovirulent or apathogenic. Previous studies implicated the type I interferon (IFN) response as being a major factor in controlling infection by apathogenic isolates. To further investigate the possibility that the host IFN-beta response underlies the pathogenicity of the two HVP2 subtypes, the susceptibility of mice lacking the IFN-beta receptor (IFNAR(-/-)) to infection was examined. Apathogenic isolates of HVP2 (HVP2ap) replicated in IFNAR(-/-) primary mouse dermal fibroblast (PMDF) cultures as well as neurovirulent (HVP2nv) isolates. IFNAR(-/-) mice were also susceptible to lethal infection by HVP2ap isolates. Unlike Balb/c or parental 129 mice, LD(50) and ID(50) values for HVP2ap were the same in IFNAR(-/-) mice indicating that in these mice infection always progressed to death. HVP2ap replicated in the skin at the site of inoculation and invaded dorsal root ganglia as efficiently as HVP2nv in IFNAR(-/-) mice. Since the virion host shutoff (vhs) protein encoded by the UL41 gene of herpes simplex virus has been implicated in circumventing the host IFN-beta response and the phenotype of UL41 deletion mutants of HSV is very similar to that of HVP2ap isolates, the UL41 gene was deleted from HVP2nv (Delta 41) and replaced with the UL41 ORF from HVP2ap (Delta 41C). Like the parental HVP2nv virus, the Delta 41C recombinant replicated efficiently in Balb/c PMDFs and did not induce a strong IFN-beta response. The neuropathogenicity of the Delta 41C recombinant was also the same as the parental HVP2nv virus in Balb/c mice, indicating that the vhs protein does not underlie the different neuropathogenic phenotype of HVP2ap and HVP2nv. In contrast, the Delta 41 deletion virus induced a strong IFN-beta response but was still able to undergo multiple rounds of replication in PMDF cultures, albeit at a slower pace than the parental HVP2nv. This was reflected in vivo as the Delta 41 mutant had an LD(50) equivalent to that of the parental HVP2nv virus although the time to death was longer. These results indicate that while the vhs protein is involved in preventing and/or suppressing an IFN-beta response, it is not responsible for the ability of HVP2nv to overcome IFN-beta induced resistance of uninfected cells and does not underlie the divergent pathogenicity of the two HVP2 subtypes in mice.
authors.affiliation: Department of Veterinary Pathobiology, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK 74078, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Rogers
authors.forename: M
authors.initials: M
authors.lastname: Deatheridge
authors.forename: M A
authors.initials: MA
authors.lastname: Breshears
authors.forename: S
authors.initials: S
authors.lastname: Chapman
authors.forename: D
authors.initials: D
authors.lastname: Black
authors.forename: J W
authors.initials: JW
authors.lastname: Ritchey
authors.forename: M
authors.initials: M
authors.lastname: Payton
authors.forename: R
authors.initials: R
authors.lastname: Eberle
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D002490:Central Nervous System / Q000821:virology; D002522:Chlorocebus aethiops; D005260:Female; D006561:Herpes Simplex / Q000276:immunology*; D016899:Interferon-beta / Q000276:immunology*; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D018139:Simplexvirus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics; D014774:Virulence; D014779:Virus Replication
chemical_list: D014764:Viral Proteins; C064566:herpes simplex virus type 2 protein UL41; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta