Pathogenesis of HCV in a Novel Mouse Model

描述（申请人提供）：该项目扩展了我们在相关体内模型中研究人类感染性疾病和治疗的长期兴趣。艾滋病毒（人类免疫缺陷病毒）和丙型肝炎病毒（丙型肝炎病毒）的双重感染是非常普遍的，由于共同的传播途径。在一些最近的流行病学研究中，HIV-1合并感染与HCV/HBV感染患者的肝脏疾病进展加速相关。因此，迫切需要一种研究HCV/HIV免疫发病机制的小动物模型。目前所有的小鼠模型都只允许在没有功能性免疫系统的情况下复制HCV。这些模型对于研究宿主免疫应答、它们对HCV发病机制的贡献和潜在的免疫学方法是没有用的。Rag 2-γ C双敲除（DKO）小鼠缺乏T/B和NK细胞，并且允许用人HSC（DKO-hu HSC）开发功能性人免疫系统。正常人T、B和树突细胞存在于淋巴组织如胸腺、脾、外周血（PB）、肝和淋巴结（LN）中。我们还表明，DKO-hu-HSC小鼠支持PB/血浆中具有高病毒血症的HIV-1感染。HIV-1以剂量依赖性方式逐渐耗尽人CD 4 + T细胞。此外，HIV-1感染在感染的HSC-DKO小鼠中持续>20周，在淋巴组织中具有感染性HIV-1。此外，HIV-1或EBV感染诱导人免疫应答。最后，人肝细胞也与人免疫系统共移植到与人胎肝衍生的肝细胞祖细胞和CD 34 + HSC细胞共移植的DKO小鼠（DKO-hu HSC/Hep小鼠）中。 该项目的长期目标是建立相关的小鼠模型以研究HCV的感染和免疫发病机制，并测试新的基于免疫的治疗方法以克服免疫耐受、炎症、纤维化和HCC。我们将首先建立DKO-hu HSC/Hep模型，用于研究HCV感染和发病机制。我们将研究HCV复制和发病机制的存在或不存在的HIV-1的共同感染在体内的模型。我还建议通过选择性消耗鼠肝细胞并促进DKO-hu HSC/Hep小鼠中的人肝细胞来增加DKO-hu HSC/Hep小鼠中的人肝细胞植入。这些研究将为未来的研究奠定基础，并为控制HCV疾病的新治疗策略提供启示。该模型也将用于测试新的抗HCV（HCC）疗法。 项目简介：本项目将建立一种新的动物模型，用于研究人类肝细胞发育和HCV感染及发病机制。我们将研究HCV的复制和发病机制，在缺乏或存在一个完整的人体免疫系统在体内的模型。这些研究将为未来的研究奠定基础，并为控制HCV疾病的新治疗策略提供启示。

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.