Human/Pig Model of Hepatitis C Virus for New Vaccines

描述(申请人提供)：丙型肝炎病毒(丙型肝炎病毒)已成为一个主要的公共卫生问题。在世界范围内，多达2亿人被感染。在美国，估计有390万人感染，其中270万美国人慢性感染。患者的免疫反应决定了患者是否治愈了病毒，是否发展为终生感染，或者是否发展为严重的肝病。由于缺乏合适的动物模型，丙型肝炎病毒的治疗和预防方面的进展受到严重阻碍。黑猩猩是除人类以外唯一感染丙型肝炎病毒的动物。然而，其发病机制与人类肝炎不同。此外，黑猩猩的伦理和可获得性限制了可以进行的研究。最近，通过将人肝细胞移植到免疫缺陷小鼠体内，建立了一种很有前途的模型。然而，这个模型不能评估对病毒或疫苗的免疫反应。我们开发了将人肝细胞移植到免疫能力强的猪身上的技术。这些创新包括在子宫内将细胞移植到胎猪体内，以及开发独特的转基因猪，以促进人类肝细胞的生长。本研究将丙型肝炎病毒接种于人肝细胞杂交猪体内，评价病毒的增殖情况，监测病毒的持久性和肝病，并对其免疫应答进行表征。丙型肝炎病毒的大动物免疫成分模型将有助于更好地了解丙型肝炎病毒的致病机制，开发更有效的疫苗和免疫治疗方法。

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) has emerged as a major public health problem. World wide, as many as 200 million people are infected. In the United States, an estimated 3.9 million are infected, with 2.7 million Americans chronically infected. The immune response of the patient determines if the patient is cured of the virus, develops a lifelong infection, or develops severe liver disease. Progress in the treatment and prevention of HCV is severely hampered by the lack of a suitable animal model. Chimpanzees are the only animals other than humans that are infected with HCV. The pathogenesis differs from human hepatitis, however. Furthermore, the ethics and availability of chimpanzees limits the studies that can be done. A promising model was recently developed by engrafting human hepatocytes in immune deficient mice. This model, however, cannot assess the immune response to the virus or vaccines. We have developed technology for engrafting human liver cells in immune competent pigs. The innovations include transplanting cells into fetal pigs in utero and the development of unique transgenic pigs that enhance the growth of human liver cells. This study will inoculate HCV into hybrid swine with human liver cells and evaluate the virus proliferation, monitor the persistence of the virus and liver disease, and characterize the immune response. A large animal immune compentent model of HCV will lead to a better understanding of the pathogenesis of hepatitis C virus and to more effective vaccines and immune therapy.