Role of HSV Induced RNA Degradation in Pathogenesis

HSV 诱导的 RNA 降解在发病机制中的作用

• 批准号: 6858529
• 负责人: David A Leib
• 金额: $ 30.6万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6858529
• 关键词: antigen presentation; gene expression; herpes simplex virus 1; herpes simplex virus 2; host organism interaction; immunity; interferons; keratitis; laboratory mouse; latent virus infection; neurons; neurotropic virus; ocular herpes; polymerase chain reaction; protein kinase; tissue /cell culture; virion; virus RNA; virus cytopathogenic effect; virus protein

DESCRIPTION (provided by applicant): Herpes simplex virus (HSV) keratitis is a leading cause of non-traumatic blindness in developed countries, with more than 200,000 cases per year in the USA. HSV can cause a variety of ocular diseases in humans ranging from self-limiting dendritic epithelial keratitis, conjunctivitis, and blepharitis to necrotizing stromal keratitis. In addition, HSV commonly causes cold sores, genital sores, and is a leading cause of viral encephalitis. The life cycles of HSV and other neurotropic herpesviruses are characterized by a lytic phase of infection at peripheral sites such as the cornea and skin during which all virus genes are expressed, and a latent phase of infection in neurons, during which gene expression is extremely limited. Latency represents a lifelong source of virus which can reactivate periodically causing severe ocular and other mucocutaneous damage, and the ability to establish lifelong latency renders HSV resistant to cure. One hallmark of the neurotropic herpesviruses is their ability to rapidly shut off macromolecular synthesis in the cells that they infect. For HSV type 1 (HSV-1) and HSV-2 the gene responsible for this shutoff is the product of the UL41 gene known as the virion host shutoff protein or vhs. All of the neurotropic herpesviruses have a homolog of the UL41 gene, although the reason for this gene conservation among viruses that establish latency in neurons is not known. Our previously funded studies have shown that vhs activity plays an essential role in infection and damage of the eye, in the development of periocular disease, and in the establishment of latency. We have defined a domain of vhs that is critical for its interaction with VP16 and thereby regulates both its the packaging and activity. We have also shown that vhs activity can alter that magnitude of immune responses to HSV. In addition we have shown that viruses deficient in vhs are effective vaccines for the prevention of recurrent herpetic infections. These accomplishments are in complete accordance with the stated research goals of the Corneal Diseases Program of the NEI. The objectives of this proposal are to build upon our previous findings and further investigate the mechanisms of action of the multifunctional vhs protein and its impact upon pathogenesis and ocular disease. We address the hypothesis is that vhs helps render HSV resistant to interferon through its ability to alter the activity of the interferon-induced kinase PKR. In addition, we test the hypothesis that vhs activity alters the recognition of virus-infected cells through control of antigen presentation, thereby shaping the adaptive immune response in favor of the virus. Finally we will identify the domains of vhs, which are important for the interaction of HSV with neurons, the site of latency for the virus, and identify how HSV and vhs alter gene expression patterns in neurons. We reason that a better definition of the mechanisms and domains of vhs function will provide targets for therapeutic intervention against HSV ocular disease, as well as aiding in the design of HSV vaccines.

描述（由申请人提供）：单纯疱疹病毒（HSV）角膜炎是发达国家非外伤性失明的主要原因，在美国每年有超过 200,000 例病例。 HSV 可引起人类多种眼部疾病，从自限性树突状上皮性角膜炎、结膜炎、睑缘炎到坏死性基质角膜炎。此外，HSV 通常会引起唇疱疹、生殖器溃疡，并且是病毒性脑炎的主要原因。 HSV和其他嗜神经性疱疹病毒的生命周期的特点是在角膜和皮肤等周围部位感染的裂解期，在此期间所有病毒基因都表达，以及在神经元感染的潜伏期，在此期间基因表达极其有限。潜伏期代表了病毒的终生来源，它可以定期重新激活，造成严重的眼部和其他皮肤粘膜损伤，而建立终生潜伏期的能力使 HSV 难以治愈。 嗜神经性疱疹病毒的特点之一是它们能够快速关闭其感染的细胞中的大分子合成。对于 1 型 HSV (HSV-1) 和 HSV-2，负责这种关闭的基因是 UL41 基因的产物，称为病毒体宿主关闭蛋白或 vhs。所有嗜神经性疱疹病毒都具有 UL41 基因的同源物，尽管在神经元中建立潜伏期的病毒之间这种基因保守的原因尚不清楚。我们之前资助的研究表明，vhs 活动在眼睛的感染和损伤、眼周疾病的发展以及潜伏期的建立中发挥着重要作用。我们定义了一个 vhs 域，该域对于其与 VP16 的相互作用至关重要，从而调节其包装和活性。我们还表明，vhs 活性可以改变对 HSV 的免疫反应程度。此外，我们还表明，缺乏 vhs 的病毒是预防复发性疱疹感染的有效疫苗。这些成果完全符合NEI角膜疾病项目既定的研究目标。 该提案的目的是基于我们之前的发现，进一步研究多功能 vhs 蛋白的作用机制及其对发病机制和眼部疾病的影响。我们提出的假设是，vhs 通过改变干扰素诱导的激酶 PKR 的活性，有助于使 HSV 对干扰素产生抗性。此外，我们还测试了这样的假设：vhs 活性通过控制抗原呈递来改变病毒感染细胞的识别，从而形成有利于病毒的适应性免疫反应。最后，我们将确定 vhs 的结构域（对于 HSV 与神经元的相互作用非常重要）、病毒的潜伏位点，并确定 HSV 和 vhs 如何改变神经元中的基因表达模式。我们认为，更好地定义 vhs 功能的机制和领域将为 HSV 眼部疾病的治疗干预提供目标，并有助于 HSV 疫苗的设计。