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

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 单纯疱疹病毒（HSV）是一种常见且重要的病原体，可导致感冒、生殖器疮和失明。 HSV 的生命周期有两个不同的阶段：裂解感染和潜伏感染。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，可强烈反式激活病毒基因表达、降解核结构域 (ND) 10 中的细胞蛋白，并抑制细胞干扰素 (IFN) 的抗病毒反应。 IFN 是分泌的细胞免疫调节因子，可上调 ND10 相关蛋白的表达，从而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 IFN 介导的 HSV 复制抑制中发挥重要作用。因此，ICP0 和 PML 通过 IFN 的相互作用可能控制 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。 该提案的目的是确定 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 损害 PML 的抗病毒活性，而 PML 是有效病毒复制所必需的。 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（目标 1）和 ICP0（目标 2）基序在调节病毒宿主反应中的贡献。 这些研究的结果预计将带来新的抗病毒疗法。

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.