Functional inaccessibility of quiescent herpes simplex virus genomes
Functional inaccessibility of quiescent herpes simplex virus genomes
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DOI：
10.1186/1743-422x-2-85
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发表时间：
2005-01-01
期刊：
影响因子：
4.8
通讯作者：
Smiley, James R.
中科院分区：
文献类型：
--
作者：
Minaker, Rebecca L.;Mossman, Karen L.;Smiley, James R.
背景：在人类成纤维细胞感染的早期阶段，新递送的单纯疱疹病毒基因组受到抑制。这种宿主防御策略可以限制病毒复制，并导致静止病毒基因组的长期持续存在。病毒立即早期蛋白ICP0的作用是否定这种负调控，从而促进病毒复制周期的开始。虽然很少有机制的细节是可用的，主机抑制机制已被提出组装病毒基因组成一个全球性的不可访问的配置类似异染色质，阻止访问大多数或所有的反式作用因子。这一假设的最有力证据是ICP0缺陷型病毒不能重新激活静止的病毒基因组，尽管其能够在足够高的感染复数下进行生产性感染。然而，最近的研究表明，静止感染诱导有效的抗病毒状态，并且ICP0在解除这种宿主抗病毒反应中起着关键作用。这些发现提出了一种可能性，即含有静止病毒基因组的细胞可能对ICP0缺陷型病毒的重复感染难以抵抗，这可能为此类病毒无法触发再激活提供了另一种解释。因此，我们问，如果ICP0缺陷型病毒是能够在细胞中复制，含有静止病毒genomes.Results：我们发现，ICP0缺陷型单纯疱疹病毒是能够感染静止感染的细胞，导致表达和复制的超感染病毒基因组。尽管这种生产性感染，居民静止的病毒基因组既不表达也不复制，除非ICP0提供的trans.Conclusion：这些数据的文件，静止的HSV基因组未能响应的病毒修饰的宿主转录装置或病毒DNA复制机器提供的反式生产性HSV感染在ICP0的情况下。这些结果表明，全球镇压HSV基因组静止的基础上，并表明，ICP0诱导通过克服这种全球障碍的反式作用因子的访问重新激活。
Background: Newly delivered herpes simplex virus genomes are subject to repression during the early stages of infection of human fibroblasts. This host defence strategy can limit virus replication and lead to long-term persistence of quiescent viral genomes. The viral immediate-early protein ICP0 acts to negate this negative regulation, thereby facilitating the onset of the viral replication cycle. Although few mechanistic details are available, the host repression machinery has been proposed to assemble the viral genome into a globally inaccessible configuration analogous to heterochromatin, blocking access to most or all trans-acting factors. The strongest evidence for this hypothesis is that ICP0-deficient virus is unable to reactivate quiescent viral genomes, despite its ability to undergo productive infection given a sufficiently high multiplicity of infection. However, recent studies have shown that quiescent infection induces a potent antiviral state, and that ICP0 plays a key role in disarming such host antiviral responses. These findings raise the possibility that cells containing quiescent viral genomes may be refractory to superinfection by ICP0-deficient virus, potentially providing an alternative explanation for the inability of such viruses to trigger reactivation. We therefore asked if ICP0-deficient virus is capable of replicating in cells that contain quiescent viral genomes.Results: We found that ICP0-deficient herpes simplex virus is able to infect quiescently infected cells, leading to expression and replication of the superinfecting viral genome. Despite this productive infection, the resident quiescent viral genome was neither expressed nor replicated, unless ICP0 was provided in trans.Conclusion: These data document that quiescent HSV genomes fail to respond to the virally modified host transcriptional apparatus or viral DNA replication machinery provided in trans by productive HSV infection in the absence of ICP0. These results point to global repression as the basis for HSV genome quiescence, and indicate that ICP0 induces reactivation by overcoming this global barrier to the access of trans-acting factors.