INNATE IMMUNE DEFENSE AGAINST HCV and HIV: THE CHIMERIC MOUSE MODEL

项目说明 暴露于丙型肝炎病毒可导致急性、自行解决的感染，但在大多数情况下 感染将进展到以持续的病毒RNA复制为特征的慢性状态。该进程 丙型肝炎病毒和丙型肝炎病毒感染后对急性或慢性感染后果的影响尚未确定。 我们的研究表明，固有的细胞内抗病毒防御可以通过以下方式控制丙型肝炎病毒RNA的复制 干扰素调节因子(IRF)激活的病原体信号通路。这些通路被触发 视黄酸诱导基因-L、TLR3和蛋白激酶R通过不同的过程 (PKR)诱导I型干扰素产生的IRF反式激活及靶基因的表达 控制病毒感染的基因。我们的体外研究表明，丙型肝炎病毒可以战胜这种宿主。 NS3/4A蛋白和NS5A蛋白分别阻断信号转导的反应 通过RIG-I和TLR3通路，抑制PKR信号转导作用。该项目将调查 假设丙型肝炎病毒调节固有的细胞内防御控制感染的结果。我们的 特定的目标旨在确定控制宿主对感染的反应的病毒/宿主界面。 我们的研究将使用嵌合小鼠和丙型肝炎病毒复制子培养系统来定义 传递和调节针对丙型肝炎病毒和丙型肝炎病毒/艾滋病毒的天然抗病毒防御的病毒和宿主参数 体内合并感染和体外抗病毒效应。AIM 1研究将定义病毒反应 体内信号传递宿主防御和控制感染结果的细胞通路。Aim 2研究将定义 NS3/4A和NS5A中的病毒基因元件对宿主防御信号和 IRF在体内发挥作用。这项工作将以使用NS3蛋白酶抑制剂和干扰素治疗为特色 应用于确定NS3/4A或NS5A的治疗调节如何阻断宿主防御 影响宿主对感染的反应。AIM 3研究将包括途径的体外方法 验证和基因功能分析以确定宿主的抗病毒效应途径和基因 控制丙型肝炎病毒和/或艾滋病毒/丙型肝炎病毒RNA复制和感染的反应。 演出场地 华盛顿大学，西雅图，华盛顿州，分包给艾伯塔大学，埃德蒙顿，艾伯塔省， 加拿大 首席调查员/方案主任(最后、第一、中间)：盖尔，Michael J. 初步预算期明细预算 仅直接成本

Description of Project Exposure to hepatitis C virus can lead to an acute, self-resolving infection but in most cases acute infection will progress to a chronic state characterized by persistent viral RNA replication. The proceses that effect acute or chronic infection outcome after HCV and HCV-HIV exposure have not been defined. Our studies indicate that innate intracellular antiviral defenses can control HCV RNA replication through pathogen signaling pathways of interferon regulatory factor (IRF) activation. These pathways are triggered through distinct processes by retinoic acid inducible gene-l, Toll-like receptor (TLR)3, and protein kinase R (PKR) to induce IRF transactivation of type I interferon (IFN) production and the expression of target genes that control virus infection. Our in vitro studies have shown that HCV can overcome this host response through the actions of the NS3/4A protease and the NS5A protein to respectively block signaling by RIG-I and TLR3 pathways, and to inhibit PKR signaling actions. This project will investigate the hypothesis that HCV regulation of innate intracellular defenses controls the outcome of infection. Our Specific Aims are designed to identify the virus/host interface that controls the host response to infection. Our studies will feature the use of the chimeric mouse and HCV replicon culture systems to define the viral and host parameters that impart and regulate innate antiviral defenses against HCV and HCV/HIV co-infection in vivo and antiviral effector actions in vitro. Aim 1 studies will define the virus-responsive cellular pathways that signal host defense and control infection outcome in vivo. Aim 2 studies will define the viral genetic elements within NS3/4A and NS5A that impart regulation of host defense signaling and IRF function in vivo. This work will feature the use of an NS3 protease inhibitor and IFN therapy applications to determine how therapeutic modulation of the NS3/4A or NS5A blockades to host defense affect the host response to infection. Aim 3 studies will comprise in vitro approaches for pathway validation and gene function analysis to define the antiviral effector pathways and genes of the host response that control HCV and/or HIV/HCV RNA replication and infection. Perfomance Sites University of Washington, Seattle, WA with subcontract to University of Alberta, Edmonton, Alberta, Canada Principal Investigator/ProgramDirector (Last, First, Middle): GALE, Michael J., DETAILED BUDGET FOR INITIAL BUDGET PERIOD DIRECT COSTS ONLY