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: 7207478
• 负责人: JIAREN SUN
• 金额: $ 33.98万
• 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 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7207478
• 关键词: Address; Adenoviruses; Adopted; American; Animal Model; Animal Viruses; 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; Elevation; Enzymes; Epitopes; Estrogen Receptors; Fatty Liver; Fluorescence Resonance Energy Transfer; Future; Gene Expression; Genes; 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; Numbers; Outcome; Pathogenesis; Patients; Persons; Phase; Polymerase Chain Reaction; Process; Production; Prophylactic treatment; Receptor Gene; Reporter; Research; Research Personnel; Role; Severity of illness; Signaling Molecule; Structural Genes; Structural Protein; System; T-Lymphocyte; TNFRSF5 gene; Tamoxifen; Technology; Testing; Therapeutic immunosuppression; 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; gene induction; immune function; in vivo; insight; intrahepatic; liver transplantation; mouse model; novel; novel therapeutics; protein expression; research study; response; virus core; virus pathogenesis

DESCRIPTION (provided by applicant): 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.

描述(申请人提供)：近400万美国人目前感染丙型肝炎病毒(丙型肝炎病毒)。丙型肝炎病毒感染每年造成约8,000-10,000人死亡，是美国肝移植的主要原因。目前还没有控制丙型肝炎的疫苗，少数人感染了丙肝。丙型肝炎病毒在最初的感染过程中会战胜病毒，并将其从血液中清除。其余75%-85%的人发展为慢性感染。这种疾病的严重程度因人而异。病毒持续、疾病进展和潜在的病毒/宿主靶点作为新的治疗方法的分子基础尚不清楚。我们假设，实质性的丙型肝炎病毒抗原提呈导致不适当的T细胞功能有助于免疫介导的肝脏炎症，并且病毒蛋白的直接免疫抑制是丙型肝炎病毒生存综合策略的一个组成部分。我们将使用三种互补的方法来检验这些假设：1)为了测试免疫共刺激分子(例如CD40)在丙型肝炎病毒相关肝损伤中的功能，我们将建立一个有条件地在肝脏中表达丙型肝炎病毒结构蛋白和CD40分子的小鼠谱系。这些小鼠的肝脏病理变化、肝脏T细胞启动和效应功能将通过流式细胞仪、ELISPOT和免疫组织学分析进行测量。2)为了检测丙型肝炎病毒非结构蛋白(NS)，尤其是NS3蛋白是否干扰宿主的抗病毒反应，导致病毒持续存在，我们将产生受新的三苯氧胺诱导系统控制的有条件表达的丙型肝炎病毒-NS基因的小鼠。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，以响应肝脏中的病毒挑战。这些动物的肝脏损伤和病毒持久性将通过生化、组织病理学和免疫化学以及实时PCR分析来确定。3)最后，我们将考察丙型肝炎病毒-S基因和-NS基因在肝脏条件表达丙型肝炎病毒全基因动物的疾病发病机制和病毒持久性方面的协同作用。总补体丙型肝炎病毒蛋白的免疫抑制效应将在病毒攻击后进行测试。这些研究将提供有关体内病毒持续存在和疾病进展的分子机制的重要信息，并可能有助于设计未来针对特定候选基因的阻断策略。