Immune Mechanisms of HCV Persistence and Pathogenesis

HCV 持续存在和发病机制的免疫机制

• 批准号: 8212128
• 负责人: JIAREN SUN
• 金额: $ 32.67万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212128
• 关键词: Address; Adenoviruses; Adopted; American; Animal Model; Animals; Antigen Presentation; Antiviral Agents; Antiviral Response; Area; Biochemical; Biological Assay; Blood Circulation; Bone Marrow; Breeding; CD40 Antigens; Cell physiology; Cessation of life; Chimeric Proteins; Chronic; Complement; Complex; Disease; Disease Progression; Enzymes; Epitopes; Estrogen Receptors; Fatty Liver; Fluorescence Resonance Energy Transfer; Future; Gene Expression; Genes; HCV Animal Models; HLA-A2.1; Hepatic; Hepatitis C; Hepatitis C Therapeutics; Hepatitis C virus; Host Defense; Human; Human papillomavirus 16 E1 protein; Immune; Immune response; Immune system; Immunologics; Immunosuppression; Infection; Inflammation; Injury; Interferon-alpha; Interferons; LacZ Genes; Liver; Measures; Mediating; Molecular; Mus; Mutate; Myelogenous; Natural Killer Cells; Nonstructural Protein; Outcome; Pathogenesis; Patients; Persons; Phase; Process; Production; Prophylactic treatment; Reporter; Research; Research Personnel; Role; Severity of illness; Signaling Molecule; Structural Protein; System; T cell response; T-Lymphocyte; TNFRSF5 gene; Tamoxifen; Technology; Testing; The Sun; Time; Transgenes; Transgenic Mice; Transgenic Organisms; United States; Vaccines; Viral; Viral Antigens; Viral Pathogenesis; Viral Proteins; Virus; Western Blotting; Work; base; defense response; design; enzyme linked immunospot assay; flexibility; gene induction; hepatitis C virus nucleocapsid protein; immune function; in vivo; insight; intrahepatic; liver transplantation; mouse model; new therapeutic target; novel; protein expression; protein function; research study; response; virus pathogenesis; Address; Adenoviruses; Adopted; American; Animal Model; Animals; Antigen Presentation; Antiviral Agents; Antiviral Response; Area; Biochemical; Biological Assay; Blood Circulation; Bone Marrow; Breeding; CD40 Antigens; Cell physiology; Cessation of life; Chimeric Proteins; Chronic; Complement; Complex; Disease; Disease Progression; Enzymes; Epitopes; Estrogen Receptors; Fatty Liver; Fluorescence Resonance Energy Transfer; Future; Gene Expression; Genes; HCV Animal Models; HLA-A2.1; Hepatic; Hepatitis C; Hepatitis C Therapeutics; Hepatitis C virus; Host Defense; Human; Human papillomavirus 16 E1 protein; Immune; Immune response; Immune system; Immunologics; Immunosuppression; Infection; Inflammation; Injury; Interferon-alpha; Interferons; LacZ Genes; Liver; Measures; Mediating; Molecular; Mus; Mutate; Myelogenous; Natural Killer Cells; Nonstructural Protein; Outcome; Pathogenesis; Patients; Persons; Phase; Process; Production; Prophylactic treatment; Reporter; Research; Research Personnel; Role; Severity of illness; Signaling Molecule; Structural Protein; System; T cell response; T-Lymphocyte; TNFRSF5 gene; Tamoxifen; Technology; Testing; The Sun; Time; Transgenes; Transgenic Mice; Transgenic Organisms; United States; Vaccines; Viral; Viral Antigens; Viral Pathogenesis; Viral Proteins; Virus; Western Blotting; Work; base; defense response; design; enzyme linked immunospot assay; flexibility; gene induction; hepatitis C virus nucleocapsid protein; immune function; in vivo; insight; intrahepatic; liver transplantation; mouse model; new therapeutic target; novel; protein expression; protein function; research study; response; virus pathogenesis

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.

目前，将近400万美国人感染了丙型肝炎病毒（HCV）。 HCV感染是造成的 每年大约有8,000-10,000人死亡，这是肝脏移植的主要原因 美国。没有用于控制丙型肝炎的疫苗。 在初始感染过程中克服病毒，并从血液中清除。其余75％-85％ 发展慢性感染。疾病的严重程度因人而异。分子 病毒持久性，疾病进展和潜在病毒/宿主靶标的新疗法的基础不是 理解。我们假设实质HCV抗原表现导致不适当的T细胞 功能有助于免疫介导的肝脏炎症和病毒直接免疫抑制 蛋白质是HCV生存综合策略的组成部分。三种互补方法将是 用于检验这些假设：1）测试免疫共刺激分子的功能（例如CD40） 与HCV相关的肝损伤，我们将建立一个有条件表达HCV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T细胞启动和 这些小鼠的效应功能将通过FACS，ELISPOT和免疫组织学分析来测量。 2） 检查HCV非结构（NS）蛋白（尤其是NS3）是否干扰宿主抗病毒 导致病毒持久性的反应，我们将产生有条件表达HCV-NS基因的小鼠， 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 （IFN） - α/β和适应性免疫反应，以应对肝脏的病毒挑战。肝损伤 这些动物中的病毒持久性将由生化，组织病理学和 免疫化学和实时PCR分析。 3）最后，我们将研究HCV-S的协同作用 和NS基因关于动物的疾病发病机理和病毒持久性有条件地表达整个 肝脏中的HCV基因。总补体HCV蛋白的免疫抑制作用将测试 遵循病毒挑战。这些研究将提供有关分子的重要信息 导致病毒持久性和体内疾病进展的机制，可能有助于设计 未来的策略旨在阻止特定的候选人。