Viral and host responses to HSV infection

描述(申请人提供)：单纯疱疹病毒(HSV)是一种常见和重要的病原体，可导致人类多种疾病过程，从感冒和生殖器溃疡到失明。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，ICP0、PML和IFN之间的相互作用很可能支配HSV将建立的感染类型。病毒宿主通过干扰素应答感染所需的ICP0和PML上的机制和结构域在很大程度上尚不清楚。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上的特定基序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、生化和细胞生物学技术来识别ICP0和PML上参与调节HSV复制的基序。我们的研究结果有望导致新的抗病毒疗法，抑制或限制HSV疾病的严重程度。为此，我们的三个特定目标是：1)确定PML基序在单纯疱疹病毒感染的干扰素反应中的作用；2)确定ICP0上用于对抗宿主对感染的防御的结构域和位点；以及3)确定ICP0-PML相互作用在调节细胞抗病毒反应中的作用。这项研究的公共卫生相关性是，单纯疱疹病毒感染是西方工业化国家传染性失明的主要原因。通过这些研究，我们期望识别和表征HSV(ICP0)和其宿主(干扰素和PML)之间的关键联系，以确定HSV将建立的感染类型。这些结果可能被用于开发新的抗HSV治疗方法。

DESCRIPTION (provided by applicant): Herpes simplex virus (HSV) is a common and significant pathogen which causes a variety of disease processes in humans, ranging from cold and genital sores to 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, it is likely that the interactions between ICP0, PML, and IFNs govern the type of infection HSV will establish. The mechanisms and domains on ICP0 and PML required in virus-host responses to infection through IFNs have been largely undetermined. The long-term objective 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 specific motifs on ICP0 and PML modulate the virus-host response. Our central hypothesis is that ICP0 impairs the anti-viral activity of PML, which, in turn, is required for efficient viral replication. To test this hypothesis, we will use a variety of genetic, biochemical, and cell biology techniques to identify motifs on ICP0 and PML that participate in regulating HSV replication. Results from our studies are expected to lead to novel anti-viral therapies that inhibit or limit the severity of HSV diseases. For this purpose, our three Specific Aims are to: 1) Determine the contribution of PML motifs in the IFN response to HSV infection, 2) Identify domains in and sites on ICP0 that serve to counteract host defenses to infection, and 3) Determine the role of ICP0-PML interactions in modulating the cellular anti-viral response. The public health relevance of this research is that HSV infections are the primary cause of infectious blindness in western industrialized countries. From these studies, we expect to identify and characterize crucial connections between HSV (ICP0) and its host (IFN and PML) that determine the type infection HSV will establish. These results may be used to develop novel anti-HSV treatments.