Pathogenesis of HCV in a Novel Mouse Model

描述（由申请人提供）：本项目扩展了我们长期以来对人类传染病及其相关体内模型治疗的研究兴趣。由于共享传播途径，HIV（人类免疫缺陷病毒）和HCV（丙型肝炎病毒）双重感染非常普遍。在最近的一些流行病学研究中，HIV-1合并感染与HCV/HBV感染患者的肝脏疾病加速进展相关。研究HCV/HIV免疫发病机制的小动物模型是迫切需要的。目前所有的小鼠模型都只允许在缺乏功能性免疫系统的情况下复制HCV。这些模型不能用于研究宿主免疫反应、它们对HCV发病机制的贡献和潜在的免疫治疗方法。Rag2-gammaC双敲除（DKO）小鼠缺乏T/B和NK细胞，并允许发展具有人类HSC （DKO-hu HSC）的功能性人类免疫系统。正常人的T细胞、B细胞和树突状细胞存在于胸腺、脾脏、外周血、肝脏和淋巴结等淋巴组织中。我们还发现DKO-hu-HSC小鼠在PB/血浆中支持高病毒血症的HIV-1感染。人类CD4+ T细胞以剂量依赖的方式逐渐被HIV-1耗尽。此外，感染HSC-DKO小鼠的HIV-1感染持续了100 - 20周，淋巴组织中感染HIV-1。此外，HIV-1或EBV感染诱导人类免疫反应。最后，在DKO小鼠中，人肝细胞也与人免疫系统共移植，人胎肝源性肝细胞祖细胞与CD34+ HSC细胞共移植（DKO-hu HSC/Hep小鼠）。

DESCRIPTION (provided by applicant): This project extends our long-standing interests in studying human infectious diseases and therapy in relevant in vivo models. HIV (human immunodeficiency virus) and HCV (hepatitis C virus) dual infection is highly prevalent as a result of shared transmission routes. In a number of recent epidemiological studies, HIV-1 co-infection has been correlated with accelerated liver disease progression in HCV/HBV infected patients. A small animal model for studying HCV/HIV immuno-pathogenesis is urgently needed. All current mouse models allow only HCV replication in the absence of a functional immune system. Those models are not useful to study host immune responses, their contributions to HCV pathogenesis and potential immunotherapeutic approaches. The Rag2-gammaC double knockout (DKO) mouse lacks T/B and NK cells, and allows development of a functional human immune system with human HSC (DKO-hu HSC). Normal human T, B, and dendritic cells are present in lymphoid tissues such as thymus, spleen, peripheral blood (PB), liver and lymph nodes (LN). We also show that DKO-hu-HSC mice support HIV-1 infection with high viremia in the PB/plasma. Human CD4+ T cells are gradually depleted by HIV-1 in a dose-dependent manner. In addition, HIV-1 infection persisted in infected HSC-DKO mice for >20 weeks, with infectious HIV-1 in lymphoid tissues. Furthermore, HIV-1 or EBV infection induces human immune responses. Lastly, human hepatocytes are also co-engrafted with human immune system in the DKO mouse co-transplanted with human fetal liver derived hepatocyte progenitor cells with CD34+ HSC cells (DKO-hu HSC/Hep mouse). The long-term goals of this project are to establish a relevant mouse model to study the infection and immuno- pathogenesis of HCV, and to test novel immune-based therapeutics to overcome immune tolerance, inflammation, fibrosis and HCC. We will first establish the DKO-hu HSC/Hep model for studying HCV infection and pathogenesis. We will investigate HCV replication and pathogenesis in the absence or presence of HIV-1 co-infection in vivo in the model. I also propose to increase human hepatocyte engraftment in the DKO-hu HSC/Hep mouse by selectively depleting murine hepatocytes and promoting human hepatocytes in the DKO- hu HSC/Hep mouse. These studies will establish the foundation for future study and shed light on novel therapeutic strategies for controlling HCV diseases. This model will also be useful to test novel anti-HCV (HCC) therapeutics. Project Narrative: This project will establish a novel animal model for studying human hepatocyte development and HCV infection and pathogenesis. We will investigate HCV replication and pathogenesis in the absence or presence of an intact human immune system in vivo in the model. These studies will establish the foundation for future study and shed light on novel therapeutic strategies for controlling HCV diseases.