INBRE: KU-L: VIRAL AND HOST RESPONSES TO HSV INFECTION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 单纯疱疹病毒(HSV)是一种常见而重要的病原体，可引起感冒、生殖器溃疡和失明。单纯疱疹病毒的生命周期有两个截然不同的阶段：裂解感染和潜伏感染。在决定裂解感染和潜伏感染之间切换的关键HSV蛋白是感染细胞蛋白0(ICP0)。ICP0是一种110 KDa的核磷蛋白，能强烈反式激活病毒基因表达，降解核区(ND)10中的细胞蛋白，并抑制细胞干扰素(IFN)的抗病毒反应。IFN是一种分泌的细胞免疫调节因子，可上调ND10相关蛋白的表达，以限制病毒的传播和复制。遗传学研究表明，ND10相关蛋白早幼粒细胞白血病(PML)在干扰素介导的抑制HSV复制中起重要作用。因此，通过IFN的ICP0和PML相互作用可能控制HSV将建立的感染类型。我们研究的长期目标是在分子水平上了解病毒-细胞相互作用如何影响HSV感染。这项建议的目的是确定ICP0和PML相互作用如何调节病毒-宿主反应。我们的中心假设是ICP0削弱了PML的抗病毒活性，而这反过来又是有效的病毒复制所必需的。为了验证这一假设，我们将使用各种遗传、生化和细胞生物学方法。为此，我们将确定PML(Aim 1)和ICP0(Aim 2)基序在调节病毒宿主反应中的作用。这些研究的结果有望导致新的抗病毒疗法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Herpes simplex virus (HSV) is a common and significant pathogen, which causes cold and genital sores and blindness. The lifecycle of HSV has two distinct phases: lytic and latent infections. A pivotal HSV protein in determining the switch between lytic and latent infections is infected cell protein 0 (ICP0). ICP0 is a 110-KDa nuclear phosphoprotein that strongly transactivates viral gene expression, degrades cellular proteins in nuclear domain (ND) 10, and inhibits the anti-viral response of cellular interferons (IFNs). IFNs are secreted cellular immunomodulatory factors that upregulate the expression of ND10-associated proteins to limit the spread and replication of viruses. Genetics studies have indicated that the ND10-associated protein, promyelocytic leukemia (PML), plays an important role in IFN-mediated inhibition of HSV replication. Thus, ICP0 and PML interactions via IFNs likely govern the type of infection HSV will establish. The long-term goal of our studies is to understand at the molecular level how virus-cell interactions affect HSV infection. The objective of this proposal is to determine how ICP0 and PML interactions modulate the virus-host response. Our central hypothesis is that ICP0 impairs the anti-viral activity of PML that, in turn, is required for efficient viral replication. To test this hypothesis, we will use a variety of genetic, biochemical, and cell biology approaches. For this purpose, we will determine the contributions of PML (Aim 1) and ICP0 (Aim 2) motifs in regulating the virus-host response. Results from these studies are expected to lead to novel anti-viral therapies.