Role of HSV Induced RNA Degradation in Pathogenesis

项目总结/摘要 单纯疱疹病毒（HSV）角膜炎是发达国家非创伤性失明的主要原因， 在美国有超过400，000例病例，每年约有50，000例新发和复发病例。HSV 引起多种眼部疾病，包括自限性树突状上皮角膜炎、结膜炎和 睑缘炎，严重的坏死性角膜基质炎。此外，HSV引起唇疱疹，生殖器溃疡，是一种 病毒性脑炎的主要病因HSV生命周期由粘膜部位的裂解期组成，在此期间， 所有的病毒基因都表达，在神经元中有一个潜伏期，在此期间基因表达非常活跃。 有限公司潜伏期是一个永久的水库，HSV周期性地重新激活，导致严重的 皮肤粘膜损伤再激活非常频繁，并导致病毒脱落。潜伏期使HSV 尽管有有效的抗病毒药物，但仍难以治愈，并且不存在有效的HSV疫苗。更好 治疗和理解疱疹性眼病是NEI角膜疾病计划的一个既定目标。 嗜神经性疱疹病毒迅速关闭感染细胞中的蛋白质合成。HSV的主要基因 负责这种关闭的是病毒体宿主关闭蛋白或VHS。Vhs是一种RNA酶， 宿主mRNA的不稳定。所有亲神经性疱疹病毒都有一个vhs的同系物，尽管其他种类的 人类疱疹病毒和其它重要病原体（例如SARS）使宿主mRNA不稳定。此属性是一个 关键毒力决定因子结果表明，VHS活性在感染和损伤中起着重要作用 在眼周疾病的发展中，以及在潜伏期的建立中。Vhs活性改变 先天性免疫应答的大小，我们确定了VHS内的功能域，其特征在于 结构域的关键，其活动在皮层，并表明，VHS是活跃的神经系统。此外 VHS缺陷的病毒是独特有效的治疗性疫苗（美国专利#5698431）。 我们目前的工作假设是，VHS决定了体内感染的结果，因为它能够改变 先天免疫功能和促进复制。先天免疫是决定病毒感染结果的关键 感染，以及预防动物模型中的全身性和致命性感染。最重要的是，人类 缺乏干扰素介导的抗病毒应答的人对HSV高度易感。更好地理解先天 因此需要对病毒感染作出反应。此外，一个更好的vhs函数定义将定义 作为HSV疾病治疗干预的靶点，以及帮助设计HSV疫苗。 此外，有新的证据表明，诱导宿主mRNA降解也是一种发病机制， 其他人类病原体的决定因素。病毒诱导的RNA不稳定的特异性抑制剂可能 因此具有作为广谱抗病毒药物的价值。因此，这项工作具有广泛的兴趣和应用。

Project Summary/Abstract Herpes simplex virus (HSV) keratitis is a leading cause of non-traumatic blindness in developed countries, with more than 400,000 cases in the USA, with approximately 50,000 new and recurring cases per year. HSV causes a variety of ocular diseases ranging from self-limiting dendritic epithelial keratitis, conjunctivitis, and blepharitis, to severe necrotizing stromal keratitis. In addition, HSV causes cold sores, genital sores, and is a leading cause of viral encephalitis. The HSV life cycle consists of a lytic phase at mucosal sites during which all virus genes are expressed, and a latent phase in neurons, during which gene expression is extremely limited. Latency is a permanent reservoir from which HSV periodically reactivates to cause severe mucocutaneous damage. Reactivation is very frequent and results in viral shedding. Latency renders HSV resistant to cure despite the availability of effective antiviral drugs, and no effective HSV vaccine exists. Better treatment and understanding of herpetic ocular disease is a stated goal of the NEI Corneal Diseases Program. Neurotropic herpesviruses rapidly shut off protein synthesis in infected cells. For HSV the major gene responsible for this shutoff is the virion host shutoff protein or vhs. Vhs is an RNAse, inducing rapid destabilization of host mRNAs. All neurotropic herpesviruses have a homolog of vhs although other classes of human herpesviruses and other important pathogens (e.g. SARS) destabilize host mRNA. This property is a critical virulence determinant. We showed that vhs activity plays an essential role in the infection and damage of the eye, in the development of periocular disease, and in the establishment of latency. Vhs activity alters the magnitude of the innate immune response and we identified functional domains within vhs, characterized a domain critical for its activity in the tegument, and shown that vhs is active in the nervous system. In addition viruses deficient in vhs are uniquely effective therapeutic vaccines (US Patent #5698431). Our current working hypothesis is that vhs determines the outcome of infection in vivo due to its ability to alter innate immune function and promote replication. Innate immunity is pivotal in determining the outcome of virus infection, and in the prevention of systemic and fatal infections in animal models. Most importantly, humans lacking interferon-mediated antiviral responses are highly susceptible to HSV. A better understanding of innate responses to virus infection is therefore needed. In addition, a better definition of vhs functions will define targets for therapeutic intervention against HSV diseases, as well as aid in design of HSV vaccines. Furthermore, there is emerging evidence that induction of host mRNA degradation is also a pathogenesis determinant for other human pathogens. Specific inhibitors of virus-induced RNA destabilization might therefore be of value as broad-spectrum antivirals. This work is therefore of broad interest and application.