Rogers K M, Deatheridge M, Breshears M A, Chapman S, Black D, Ritchey J W, Payton M, Eberle R
Department of Veterinary Pathobiology, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK 74078, USA.
Virology. 2009 Apr 10;386(2):280-9. doi: 10.1016/j.virol.2009.01.001. Epub 2009 Feb 11.
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.
狒狒α-疱疹病毒2型（HVP2）的分离株在小鼠中表现出两种不同表型之一：极具神经毒性或无致病性。先前的研究表明，I型干扰素（IFN）反应是控制无致病性分离株感染的主要因素。为了进一步研究宿主IFN-β反应是否是两种HVP2亚型致病性的基础，研究人员检测了缺乏IFN-β受体（IFNAR（-/-））的小鼠对感染的易感性。HVP2的无致病性分离株（HVP2ap）在IFNAR（-/-）原代小鼠皮肤成纤维细胞（PMDF）培养物中以及神经毒性（HVP2nv）分离株中均能复制。IFNAR（-/-）小鼠也易受HVP2ap分离株的致死性感染。与Balb/c或亲代129小鼠不同，HVP2ap在IFNAR（-/-）小鼠中的半数致死剂量（LD（50））和半数感染剂量（ID（50））相同，这表明在这些小鼠中感染总是会发展到死亡。在IFNAR（-/-）小鼠中，HVP2ap在接种部位的皮肤中复制，并与HVP2nv一样有效地侵入背根神经节。由于单纯疱疹病毒UL41基因编码的病毒体宿主关闭（vhs）蛋白与规避宿主IFN-β反应有关，且HSV的UL41缺失突变体的表型与HVP2ap分离株非常相似，因此从HVP2nv中删除了UL41基因（Δ41），并用HVP2ap的UL41开放阅读框（Δ41C）进行替换。与亲代HVP2nv病毒一样，Δ41C重组体在Balb/c PMDFs中高效复制，且未诱导强烈的IFN-β反应。在Balb/c小鼠中，Δ41C重组体的神经致病性也与亲代HVP2nv病毒相同，这表明vhs蛋白不是HVP2ap和HVP2nv不同神经致病表型的基础。相比之下，Δ41缺失病毒诱导了强烈的IFN-β反应，但仍能够在PMDF培养物中进行多轮复制，尽管速度比亲代HVP2nv慢。这在体内表现为，Δ41突变体的LD（50）与亲代HVP2nv病毒相当，尽管死亡时间更长。这些结果表明，虽然vhs蛋白参与预防和/或抑制IFN-β反应，但它并不负责HVP2nv克服IFN-β诱导的未感染细胞抗性的能力，也不是两种HVP2亚型在小鼠中致病性差异的基础。
