Varicella-zoster virus IE63, a major viral latency protein, is required to inhibit the alpha interferon-induced antiviral response
Varicella-zoster virus IE63, a major viral latency protein, is required to inhibit the alpha interferon-induced antiviral response
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DOI：
10.1128/jvi.00325-07
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发表时间：
2007-08-01
影响因子：
5.4
通讯作者：
Cohen, Jeffrey I.
中科院分区：
文献类型：
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作者：
Ambagala, Aruna P. N.;Cohen, Jeffrey I.
水痘带状疱疹病毒 (VZV) 开放阅读框 63 (ORF63) 是人类感觉神经节潜伏期表达最丰富的转录本。 ORF63缺失的VZV在黑色素瘤细胞和成纤维细胞中的复制以及在啮齿动物中的潜伏期受到损害。我们发现 ORF63 缺失突变体的复制在 U2OS 细胞中得到完全补充，这已被证明可以补充单纯疱疹病毒 1 型 (HSV-1) ICP0 突变体的生长。由于 HSV-1 1CP0 突变体对 α 干扰素 (IFN-ci) 高度敏感，因此我们检查了 IFN-α 对 VZV 复制的影响。 ORF63突变体在黑色素瘤细胞中的复制在IFN-α存在的情况下受到严重抑制，而其他VZV突变体的复制或亲代病毒也同样受到损害。 VZV ORF63 突变体对 IFN-γ 不过敏。 IFN-α 在转录后水平抑制感染 ORF63 突变体的细胞中的病毒基因表达。由于IFN-ot刺激可以磷酸化真核起始因子2（eIF-2α）的x亚基并抑制翻译的基因产物，因此我们确定与感染亲本病毒的细胞相比，感染ORF63突变体的细胞是否增加了eIF-2α的磷酸化。虽然在未感染的细胞或感染亲本病毒的细胞中检测不到磷酸化的eIF-2α，但它存在于感染ORF63突变体的细胞中。相反，在没有其他病毒蛋白的情况下，IE63（由 ORF63 编码）的表达会抑制 eIF-2 α 的磷酸化。由于 IFN-α 已被证明可以限制 VZV 在人类皮肤异种移植物中的复制，因此 VZV IE63 阻断细胞因子作用的能力可能在 VZV 发病机制中发挥关键作用。
Varicella-zoster virus (VZV) open reading frame 63 (ORF63) is the most abundant transcript expressed during latency in human sensory ganglia. VZV with ORF63 deleted is impaired for replication in melanoma cells and fibroblasts and for latency in rodents. We found that replication of the ORF63 deletion mutant is fully complemented in U2OS cells, which have been shown to complement the growth of herpes simplex virus type 1 (HSV-1) ICP0 mutants. Since HSV-1 1CP0 mutants are hypersensitive to alpha interferon (IFN-ci), we examined the effect of IFN-alpha on VZV replication. Replication of the ORF63 mutant in melanoma cells was severely inhibited in the presence of IFN-alpha, in contrast to other VZV mutants that were similarly impaired for replication or to parental virus. The VZV ORF63 mutant was not hypersensitive to IFN-gamma. IFN-alpha inhibited viral-gene expression in cells infected with the ORF63 mutant at a posttranscriptional level. Since IFN-ot stimulates gene products that can phosphorylate the (x subunit of eukaryotic initiation factor 2 (eIF-2 alpha) and inhibit translation, we determined whether cells infected with the ORF63 mutant had increased phosphorylation of eIF-2 alpha compared with cells infected with parental virus. While phosphorylated eIF-2 alpha was undetectable in uninfected cells or cells infected with parental virus, it was present in cells infected with the ORF63 mutant. Conversely, expression of IE63 (encoded by ORF63) in the absence of other viral proteins inhibited phosphorylation of eIF-2 alpha. Since IFN-alpha has been shown to limit VZV replication in human skin xenografts, the ability of VZV IE63 to block the effects of the cytokine may play a critical role in VZV pathogenesis.