Immune Mechanisms of HCV Persistence and Pathogenesis

近400万美国人目前感染丙型肝炎病毒(丙型肝炎病毒)。丙型肝炎病毒感染是 每年约有8,000-10,000人死亡，是美国肝移植的主要原因 美国。目前还没有控制丙型肝炎的疫苗。感染丙型肝炎病毒的少数人 在最初的感染过程中战胜病毒，并将其从血液中清除。其余75%-85% 患上慢性感染。这种疾病的严重程度因人而异。分子 病毒持久性、疾病进展和新疗法的潜在病毒/宿主靶点的基础不是 很好理解。我们假设实质性的丙型肝炎病毒抗原提呈会导致不适当的T细胞 功能参与免疫介导的肝脏炎症，并通过病毒直接免疫抑制 蛋白质是丙型肝炎病毒生存综合策略的组成部分。三种互补的方法将是 用于测试这些假设：1)测试免疫共刺激分子(例如CD40)在 ，我们将建立一个有条件地表达丙型肝炎病毒结构的小鼠谱系 肝脏中的蛋白质和CD40分子。肝脏的病理变化，肝脏T细胞的激活和 这些小鼠的效应器功能将通过流式细胞仪、ELISPOT和免疫组织学分析进行测量。2) 为了检查丙型肝炎病毒非结构蛋白(NS)，特别是NS3，是否干扰宿主抗病毒 导致病毒持续存在的反应，我们将产生有条件地表达丙型肝炎病毒NS基因的小鼠， 它们由一种新型的他莫昔芬诱导系统控制。我们将检查这些动物的干扰素 (干扰素)-α/β和适应性免疫反应，以应对肝脏中的病毒挑战。肝损伤 而病毒在这些动物中的持久性将由生化、组织病理学和 免疫化学和实时聚合酶链式反应分析。3)最后，我们将检验丙型肝炎病毒-S的协同效应 和-NS基因对动物致病机制和病毒持久性的影响 肝脏中的丙型肝炎病毒基因。将测试总补体丙型肝炎病毒蛋白的免疫抑制作用 在一场病毒式挑战之后。这些研究将提供有关分子的重要信息。 负责体内病毒持续和疾病进展的机制，并可能有助于设计 未来的战略旨在阻止特定的候选人。

Nearly 4 million Americans are currently infected with hepatitis C virus (HCV). HCV infection is responsible for approximately 8,000-10,000 deaths annually and is the leading reason for liver transplantation in the United States. There is no vaccine for the control of hepatitis C. A small number of people infected with.HCV overcome the virus during the initial infection and clear it from the bloodstream. The remaining 75%-85% develop a chronic infection. The severity of the disease varies greatly from person to person. The molecular basis for viral persistence, disease progression and potential virus/host targets for novel therapeutics is not well understood. We hypothesize that parenchymal HCV antigen presentation leading to inappropriate T cell function contributes to immune-mediated liver inflammation and that direct immunosuppression by viral proteins is a component of an integrated strategy of HCV survival. Three complementary approaches will be used to test these hypotheses: 1) To test the function of immune costimulatory molecules (e.g. CD40) in HCV-related liver injuries, we will establish a lineage of mice that conditionally express HCV structural proteins and CD40 molecules in the liver. Pathological changes in the liver, hepatic T cell priming and effector functions in these mice will be measured by FACS, ELISPOT and immunohistological analyses. 2) To examine whether HCV nonstructural (NS) proteins, especially NS3, interfere with the host antiviral responses leading to viral persistence, we will generate mice conditionally expressing HCV-NS genes, which are controlled by a novel tamoxifen-inducible system. We will examine these animals' interferon (IFN)-alpha/beta and adaptive immune responses in response to a viral challenge in the liver. Hepatic injury and viral persistence in these animals will be determined by biochemical, histopathological and immunochemical, and real-time PCR analyses. 3) Finally, we will examine the synergistic effects of HCV-S and-NS genes on disease pathogenesis and viral persistence in animals conditionally expressing the entire HCV genes in the liver. The immunosuppressive effect of the total complement HCV proteins will be tested following a viral challenge. These studies would provide important information concerning molecular mechanisms responsible for viral persistence and disease progression in vivo, and may aid in devising future strategies targeted at blocking specific candidates.