Moffat J F, Zerboni L, Kinchington P R, Grose C, Kaneshima H, Arvin A M
Department of Pediatrics, Stanford University School of Medicine, California 94305-5208, USA.
J Virol. 1998 Feb;72(2):965-74. doi: 10.1128/JVI.72.2.965-974.1998.
The SCID-hu mouse implanted with human fetal tissue is a novel model for investigating human viral pathogenesis. Infection of human skin implants was used to investigate the basis for the clinical attenuation of the varicella-zoster virus (VZV) strain, V-Oka, from which the newly licensed vaccine is made. The pathogenicity of V-Oka was compared with that of its parent, P-Oka, another low-passage clinical isolate, strain Schenke (VZV-S), and VZV-Ellen, a standard laboratory strain. The role of glycoprotein C (gC) in infectivity for human skin was assessed by using gC-negative mutants of V-Oka and VZV-Ellen. Whereas all of these VZV strains replicated well in tissue culture, only low-passage clinical isolates were fully virulent in skin, as shown by infectious virus yields and analysis of implant tissues for VZV DNA and viral protein synthesis. The infectivity of V-Oka in skin was impaired compared to that of P-Oka, providing the first evidence of a virologic basis for the clinical attenuation of V-Oka. The infectivity of V-Oka was further diminished in the absence of gC expression. All strains except gC-Ellen retained some capacity to replicate in human skin, but cell-free virus was recovered only from implants infected with P-Oka or VZV-S. Although VZV is closely related to herpes simplex virus type 1 (HSV-1) genetically, experiments in the SCID-hu model revealed differences in tropism for human cells that correlated with differences in VZV and HSV-1 disease. VZV caused extensive infection of epidermal and dermal skin cells, while HSV-1 produced small, superficial lesions restricted to the epidermis. As in VZV, gC expression was a determinant for viral replication in skin. VZV infects human CD4+ and CD8+ T cells in thymus/liver implants, but HSV-1 was detected only in epithelial cells, with no evidence of lymphotropism. These SCID-hu mouse experiments show that the clinical attenuation of the varicella vaccine can be attributed to decreased replication of V-Oka in skin and that tissue culture passage alone reduces the ability of VZV to infect human skin in vivo. Furthermore, gC, which is dispensable for replication in tissue culture, plays a critical role in the virulence of the human alphaherpesviruses VZV and HSV-1 for human skin.
植入人胎儿组织的重症联合免疫缺陷-人源化小鼠是研究人类病毒发病机制的新型模型。利用人皮肤植入物感染来研究水痘-带状疱疹病毒（VZV）V-Oka株临床减毒的基础，新获批的疫苗即基于该毒株制成。将V-Oka的致病性与其亲本P-Oka、另一低传代临床分离株申克毒株（VZV-S）以及标准实验室毒株VZV-Ellen进行比较。通过使用V-Oka和VZV-Ellen的gC阴性突变体评估糖蛋白C（gC）在感染人皮肤中的作用。尽管所有这些VZV毒株在组织培养中均能良好复制，但如感染性病毒产量以及对植入组织进行VZV DNA和病毒蛋白合成分析所示，只有低传代临床分离株在皮肤中具有完全的毒力。与P-Oka相比，V-Oka在皮肤中的感染性受损，这为V-Oka临床减毒的病毒学基础提供了首个证据。在缺乏gC表达的情况下，V-Oka的感染性进一步降低。除gC-Ellen外的所有毒株在人皮肤中仍保留一定的复制能力，但仅从感染P-Oka或VZV-S的植入物中回收了无细胞病毒。尽管VZV在基因上与单纯疱疹病毒1型（HSV-1）密切相关，但在重症联合免疫缺陷-人源化模型中的实验揭示了其对人细胞嗜性的差异，这与VZV和HSV-1疾病的差异相关。VZV引起表皮和真皮皮肤细胞的广泛感染，而HSV-1产生局限于表皮的小的浅表病变。与VZV一样，gC表达是病毒在皮肤中复制的决定因素。VZV感染胸腺/肝脏植入物中的人CD4+和CD8+ T细胞，但仅在上皮细胞中检测到HSV-1，没有嗜淋巴细胞性的证据。这些重症联合免疫缺陷-人源化小鼠实验表明，水痘疫苗的临床减毒可归因于V-Oka在皮肤中复制的减少，并且仅组织培养传代就降低了VZV在体内感染人皮肤的能力。此外，gC虽然在组织培养复制中并非必需，但在人类α疱疹病毒VZV和HSV-1对人皮肤的毒力中起关键作用。
