ICP0 antagonizes Stat 1-dependent repression of herpes simplex virus: implications for the regulation of viral latency.
ICP0 antagonizes Stat 1-dependent repression of herpes simplex virus: implications for the regulation of viral latency.
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DOI：
10.1186/1743-422x-3-44
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发表时间：
2006-06-09
期刊：
影响因子：
4.8
通讯作者：
Gebhardt BM
中科院分区：
文献类型：
--
作者：
Halford WP;Weisend C;Grace J;Soboleski M;Carr DJ;Balliet JW;Imai Y;Margolis TP;Gebhardt BM
单纯疱疹病毒1型（HSV-1）ICP 0蛋白是一种E3泛素连接酶，在HSV-1潜伏相关基因座内编码。当ICP 0不合成时，HSV-1基因组对细胞阻遏非常敏感。反过来，当ICP 0合成时，病毒复制从病毒粒子或潜伏的HSV-1基因组有效启动。本研究的目的是确定ICP 0作为病毒干扰素（IFN）拮抗剂的假定作用是否可能与ICP 0影响HSV-1的生产性复制与细胞抑制之间平衡的过程有关。HSV-1的野生型（ICP 0+）菌株在scid或rag 2-/-小鼠中产生致死性感染。ICP 0- null病毒的复制被scid或rag 2-/-小鼠的先天宿主反应迅速抑制，感染的动物在数月内保持健康。相比之下，缺乏IFN-α/β受体（rag 2-/- ifnar-/-）或Stat 1（rag 2-/-stat 1-/-）的rag 2-/-小鼠无法抑制ICP 0病毒复制，导致病毒扩散和死亡不受控制。因此，ICP 0病毒的复制在体内被依赖于IFN-α/β受体和下游转录因子Stat 1的先天免疫应答有效抑制。ICP 0作为病毒IFN拮抗剂的功能在体内是必需的，以防止先天的Stat 1依赖性宿主应答快速抑制生产性HSV-1复制。ICP 0和宿主IFN应答之间的这种拮抗关系可能与调节体内病毒感染细胞中HSV-1基因组的表达或沉默有关。这些结果也可能具有临床意义。IFN-敏感的ICP 0病毒是无毒的，建立长期潜伏感染，并诱导适应性免疫应答，对HSV-1的致死性攻击具有高度保护性。因此，ICP 0-病毒似乎具有抗疱疹病活疫苗所需的安全性和有效性特征。
The herpes simplex virus type 1 (HSV-1) ICP0 protein is an E3 ubiquitin ligase, which is encoded within the HSV-1 latency-associated locus. When ICP0 is not synthesized, the HSV-1 genome is acutely susceptible to cellular repression. Reciprocally, when ICP0 is synthesized, viral replication is efficiently initiated from virions or latent HSV-1 genomes. The current study was initiated to determine if ICP0's putative role as a viral interferon (IFN) antagonist may be relevant to the process by which ICP0 influences the balance between productive replication versus cellular repression of HSV-1. Wild-type (ICP0+) strains of HSV-1 produced lethal infections in scid or rag2-/- mice. The replication of ICP0- null viruses was rapidly repressed by the innate host response of scid or rag2-/- mice, and the infected animals remained healthy for months. In contrast, rag2-/- mice that lacked the IFN-α/β receptor (rag2-/- ifnar-/-) or Stat 1 (rag2-/- stat1-/-) failed to repress ICP0- viral replication, resulting in uncontrolled viral spread and death. Thus, the replication of ICP0- viruses is potently repressed in vivo by an innate immune response that is dependent on the IFN-α/β receptor and the downstream transcription factor, Stat 1. ICP0's function as a viral IFN antagonist is necessary in vivo to prevent an innate, Stat 1-dependent host response from rapidly repressing productive HSV-1 replication. This antagonistic relationship between ICP0 and the host IFN response may be relevant in regulating whether the HSV-1 genome is expressed, or silenced, in virus-infected cells in vivo. These results may also be clinically relevant. IFN-sensitive ICP0- viruses are avirulent, establish long-term latent infections, and induce an adaptive immune response that is highly protective against lethal challenge with HSV-1. Therefore, ICP0- viruses appear to possess the desired safety and efficacy profile of a live vaccine against herpetic disease.