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

项目概述 暴露于丙型肝炎病毒可导致急性，自我解决的感染，但在大多数情况下急性 感染将发展为以持续的病毒RNA复制为特征的慢性状态。过程 影响HCV和HCV-HIV暴露后急性或慢性感染结果的因素尚未确定。 我们的研究表明，先天性细胞内抗病毒防御可以通过以下途径控制HCV RNA复制： 干扰素调节因子（IRF）激活的病原体信号传导途径。这些通路被触发 通过维甲酸诱导基因-1、Toll样受体（TLR）3和蛋白激酶R的不同过程， (PKR)诱导IRF反式激活I型干扰素（IFN）的产生和靶点的表达 控制病毒感染的基因我们的体外研究表明，丙型肝炎病毒可以克服这一宿主 通过NS3/4A蛋白酶和NS5A蛋白的作用分别阻断信号传导的应答 通过RIG-I和TLR3途径，并抑制PKR信号传导作用。该项目将调查 HCV对先天性细胞内防御的调节控制感染结果的假说。我们 特定目标旨在识别控制宿主对感染反应的病毒/宿主界面。 我们的研究将使用嵌合小鼠和HCV复制子培养系统来确定HCV的表达。 赋予和调节针对HCV和HCV/HIV的先天抗病毒防御的病毒和宿主参数 体内共感染和体外抗病毒效应作用。目标1研究将定义病毒应答 细胞通路，在体内发出宿主防御信号并控制感染结果。目标2研究将定义 NS3/4A和NS5A内的病毒遗传元件，其赋予宿主防御信号的调节， 体内IRF功能。这项工作将采用NS3蛋白酶抑制剂和IFN治疗 应用以确定NS3/4A或NS5A的治疗性调节如何阻断宿主防御 影响宿主对感染的反应目标3研究将包括体外途径 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HCV和/或HIV/HCV RNA复制和感染的应答。 性能网站 华盛顿大学，西雅图，华盛顿州与阿尔伯塔大学，埃德蒙顿，阿尔伯塔省， 加拿大 主要研究者/项目负责人（最后，第一，中间）：GALE，Michael J.， 初步预算期的详细预算 仅直接费用

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