Murphy Jenny A, Duerst Rebecca J, Smith Tracy J, Morrison Lynda A
Department of Molecular Microbiology, Saint Louis University School of Medicine, St. Louis, Missouri 63104, USA.
J Virol. 2003 Sep;77(17):9337-45. doi: 10.1128/jvi.77.17.9337-9345.2003.
The herpes simplex virus (HSV) virion host shutoff (vhs) protein, the product of the UL41 (vhs) gene, is an important determinant of HSV virulence. vhs has been implicated in HSV interference with host antiviral immune responses, down-regulating expression of major histocompatibility complex molecules to help HSV evade host adaptive immunity. The severe attenuation of vhs-deficient viruses in vivo could reflect their inability to escape immune detection. To test this hypothesis, BALB/c or congenic SCID mice were infected intravaginally (i.vag.) with the HSV type 2 (HSV-2) vhs null mutant 333d41 or the vhs rescue virus 333d41(R). vhs-deficient virus remained severely attenuated in SCID mice compared with rescue virus, indicating that vhs regulation of adaptive immune responses does not influence HSV pathogenesis during acute infection. Innate antiviral effectors remain intact in SCID mice; prominent among these is alpha/beta interferon (IFN-alpha/beta). The attenuation of HSV-2 vhs mutants could reflect their failure to suppress IFN-alpha/beta-mediated antiviral activity. To test this hypothesis, 129 and congenic IFN-alpha/beta receptor-deficient (IFN-alpha/betaR(-/-)) mice were infected i.vag. with wild-type virus, vhs null mutants 333-vhsB or 333d41, or the vhs rescue virus 333d41(R). Whereas vhs-deficient viruses showed greatly reduced replication in the genital mucosa of 129 mice compared with wild-type or vhs rescue viruses, they were restored to nearly wild-type levels of replication in IFN-alpha/betaR(-/-) mice over the first 2 days postinfection. Only wild-type and vhs rescue viruses caused severe genital disease and hind limb paralysis in 129 mice, but infection of IFN-alpha/betaR(-/-) mice restored the virulence of vhs-deficient viruses. vhs-deficient viruses replicated as vigorously as wild-type and rescue viruses in the nervous systems of IFN-alpha/betaR(-/-) mice. Restoration was specific for the vhs mutation, because thymidine kinase-deficient HSV-2 did not regain virulence or the capacity to replicate in the nervous systems of IFN-alpha/betaR(-/-) mice. Furthermore, the defect in the IFN-alpha/beta response was required for restoration of vhs-deficient virus replication and virulence, but the IFN-alpha/beta-stimulated protein kinase R pathway was not involved. Finally, vhs of HSV-2 has a unique capacity to interfere with the IFN-alpha/beta response in vivo, because an HSV-1 vhs null mutant did not recover replication and virulence after i.vag. inoculation into IFN-alpha/betaR(-/-) mice. These results indicate that vhs plays an important role early in HSV-2 pathogenesis in vivo by interfering with the IFN-alpha/beta-mediated antiviral response.
单纯疱疹病毒（HSV）的病毒体宿主关闭（vhs）蛋白是UL41（vhs）基因的产物，是HSV毒力的重要决定因素。vhs与HSV干扰宿主抗病毒免疫反应有关，它下调主要组织相容性复合体分子的表达，以帮助HSV逃避宿主适应性免疫。vhs缺陷病毒在体内的严重减毒可能反映出它们无法逃避免疫检测。为了验证这一假设，将BALB/c或同基因SCID小鼠经阴道感染2型单纯疱疹病毒（HSV-2）的vhs缺失突变体333d41或vhs拯救病毒333d41（R）。与拯救病毒相比，vhs缺陷病毒在SCID小鼠中仍严重减毒，这表明vhs对适应性免疫反应的调节不影响急性感染期间HSV的发病机制。先天性抗病毒效应分子在SCID小鼠中保持完整；其中突出的是α/β干扰素（IFN-α/β）。HSV-2 vhs突变体的减毒可能反映出它们无法抑制IFN-α/β介导的抗病毒活性。为了验证这一假设，将129和同基因IFN-α/β受体缺陷（IFN-α/βR（-/-））小鼠经阴道感染野生型病毒、vhs缺失突变体333-vhsB或333d41，或vhs拯救病毒333d41（R）。与野生型或vhs拯救病毒相比，vhs缺陷病毒在129小鼠的生殖器黏膜中的复制大大减少，但在感染后的头2天内，它们在IFN-α/βR（-/-）小鼠中的复制恢复到接近野生型水平。只有野生型和vhs拯救病毒在129小鼠中引起严重的生殖器疾病和后肢麻痹，但IFN-α/βR（-/-）小鼠的感染恢复了vhs缺陷病毒的毒力。vhs缺陷病毒在IFN-α/βR（-/-）小鼠的神经系统中复制得与野生型和拯救病毒一样旺盛。恢复是vhs突变所特有的，因为胸苷激酶缺陷的HSV-2在IFN-α/βR（-/-）小鼠的神经系统中没有恢复毒力或复制能力。此外，IFN-α/β反应缺陷是vhs缺陷病毒复制和毒力恢复所必需的，但IFN-α/β刺激的蛋白激酶R途径未参与其中。最后，HSV-2的vhs在体内具有独特的干扰IFN-α/β反应的能力，因为HSV-1的vhs缺失突变体经阴道接种到IFN-α/βR（-/-）小鼠后没有恢复复制和毒力。这些结果表明，vhs通过干扰IFN-α/β介导的抗病毒反应在HSV-2体内发病机制的早期发挥重要作用。
