Murine model for hepatitis C virus

描述（由申请人提供）：慢性丙型肝炎病毒感染影响约3%的世界人口。尽管在过去十年中对该病毒的了解取得了进展，但丙型肝炎病毒对治疗的反应有限以及缺乏有效的疫苗仍然是主要的科学挑战。HCV发病机制的基础是免疫系统和病毒之间的相互作用。T细胞似乎在病毒的持久性和清除中起着核心作用。然而，T细胞如何对HCV感染作出反应以及病毒如何对T细胞施加影响的机制尚不清楚。这严重阻碍了免疫疗法和疫苗战略的发展。HCV免疫发病机制研究的一个主要障碍是缺乏足够和强大的细胞培养系统和小动物模型。我们的研究目标是建立一个可靠的体外和体内小鼠模型来研究HCV免疫反应。为了实现这一目标，我们已经成功地从永生化的小鼠肝细胞细胞系中建立了几种HCV复制子细胞系，并开发了一种用小鼠HCV复制子细胞系重新填充小鼠肝脏的方法。在本次应用中，我们将测试该小鼠模型研究宿主对HCV免疫反应的可行性。具体目标如下：首先，我们将利用体外细胞培养系统研究小鼠HCV特异性CD8+ T细胞与支持HCV RNA复制的目标小鼠肝细胞之间的相互作用；其次，我们将通过在小鼠肝脏中重新填充含有HCV复制子的肝细胞来建立小鼠体内模型，以研究宿主免疫反应对HCV RNA复制和肝脏病理的影响。一旦这个小鼠模型系统被实验证明是可行和可靠的，我们将进一步表征免疫活性细胞和靶肝细胞之间的相互作用。从这些研究中获得的知识可能对开发有效的免疫疗法和疫苗作出重大贡献。

DESCRIPTION (provided by applicant): Chronic hepatitis C viral infection affects approximately 3% of world's population. Despite the progress made over the past decade in understanding the virus, the limited responsiveness of HCV to therapy and the lack of an effective vaccine remain as major scientific challenges. Fundamental to the pathogenesis of HCV is the interaction between the immune system and the virus. T cells appear to play a central role in viral persistence and clearance. However, the mechanisms of how T cells respond to HCV infection and how the virus exerts influence on T cells are not understood. This seriously hampers the development of strategies for immunotherapy and vaccine. One major obstacle in HCV immunopathogenesis research is the lack of adequate and robust cell culture systems and small animal models. The goal of our research is to establish a reliable in vitro and in vivo murine model for studying HCV immune response. To achieve this end, we have successfully established several HCV replicon cell lines from immortalized mouse hepatocyte cell lines, and have developed a methodology to repopulate mouse liver with the mouse HCV replicon cell lines. In this application, we will test the feasibility of this mouse model to study the host immune response to HCV. The objective will be achieved in the following specific aims: First, we will utilize the in vitro cell culture system to investigate the interactions between murine HCV-specific CD8+ T cells and the target murine hepatocytes that support HCV RNA replication; Second, we will develop an in vivo murine model by repopulating HCV replicon-containing hepatocytes in mouse liver, to investigate the effect of the host immune response on HCV RNA replication and liver pathology. Once this mouse model system is proven to be feasible and reliable by the proposed experiments, we will further characterize the interactions between immune competent cells and target hepatocytes. The knowledge derived from these studies may contribute significantly to the development of effective immunotherapies and vaccines.