A Novel Humanized Mouse Model for Studying HIV/HCV Co-Infection and Liver Disease

描述(由申请人提供)：一种新的人源化小鼠模型，用于研究艾滋病毒/丙型肝炎联合感染和肝病个体的酒精消费与病毒联合感染和肝病的易感性增加有关。HIV-1和丙型肝炎病毒(丙型肝炎病毒)混合感染是由于共同的传播途径而高度流行的，与丙型肝炎病毒感染患者肝病进展加速相关。目前迫切需要一种允许丙型肝炎病毒和/或艾滋病病毒复制和致病的小鼠模型，以研究乙醇和艾滋病病毒混合感染对丙型肝炎病毒感染和肝脏发病的影响。Rag2-C双基因敲除(DKO)小鼠缺乏T/B和NK细胞，并允许利用人类造血干细胞(DKO-Hu HSC小鼠)发展出具有功能的人类免疫系统。正常人T、B细胞和树突状细胞存在于胸腺、脾、外周血(PB)、淋巴结(LN)以及肝脏等淋巴组织中。我们还表明，DKO-HU-HSC小鼠允许在淋巴器官和肝脏中持续高水平的HIV-1感染。人类CD4+T细胞被HIV-1以剂量依赖的方式逐渐耗尽，这与肝脏中炎性细胞因子的诱导和淋巴细胞的渗透有关。此外，在感染的DKO-Hu HSC小鼠中，HIV-1感染持续了20周，淋巴和肝脏组织中也有HIV-1感染。此外，HIV-1或EBV感染会诱导人类免疫反应。最近，我们在人肝细胞前体细胞和CD34+HSC细胞移植的DKO小鼠(DKO-Hu HSC/Hep小鼠)中，将人肝细胞和人免疫系统共移植到DKO小鼠体内。我建议对DKO-Hu HSC/Hep小鼠进行优化，通过选择性地消耗小鼠肝细胞和促进人肝细胞在DKO-Hu HSC/Hep小鼠体内提高人肝细胞的植入率。在这个模型中，我们还将研究乙醇和HIV-1混合感染如何影响丙型肝炎病毒感染和肝脏发病。本项目的长期目标是1)建立一种相关的小鼠模型，以研究丙型肝炎病毒感染和丙型肝炎病毒/艾滋病病毒混合感染的免疫发病机制；2)研究酒精对HIV或丙型肝炎病毒感染和体内肝脏发病的影响。具体地说，我们将优化DKO-Hu HSC/HEP模型，以研究丙型肝炎病毒感染和免疫发病机制。我们将建立酒精治疗对丙型肝炎病毒感染和肝脏发病机制的影响。我们还将调查HIV合并感染如何影响丙型肝炎病毒的复制和发病机制。这些研究将为未来的研究奠定基础，并为控制与艾滋病毒和/或丙型肝炎病毒感染相关的肝病提供新的治疗策略。 公共卫生相关性：该项目的长期目标是：1)建立一种新的小鼠模型，以研究丙型肝炎病毒感染和丙型肝炎病毒/艾滋病病毒混合感染的免疫发病机制；2)研究酒精如何影响艾滋病毒或丙型肝炎病毒感染和体内肝脏发病。我们将建立酒精治疗对丙型肝炎病毒感染和肝脏发病机制的影响。我们还将调查HIV合并感染如何影响丙型肝炎病毒的复制和发病机制。这些研究将为未来的研究奠定基础，并为控制与艾滋病毒和/或丙型肝炎病毒感染相关的肝病提供新的治疗策略。

DESCRIPTION (provided by applicant): A Novel Humanized Mouse Model for Studying HIV/HCV Co-Infection and Liver Disease Alcohol consumption by HIV+ individuals has been associated with increased susceptibility to viral co- infection and liver disease. HIV-1 and HCV (hepatitis C virus) coinfection, highly prevalent as a result of shared transmission routes, has been correlated with accelerated liver disease progression in HCV infected patients. A mouse model that allows HCV and/or HIV replication and pathogenesis is urgently needed to study the effect of ethanol and HIV coinfection on HCV infection and liver pathogenesis. The Rag2-C double knockout (DKO) mouse lacks T/B and NK cells, and allows development of a functional human immune system with human Hematopoietic Stem Cell (DKO-hu HSC mice). Normal human T, B, and dendritic cells are present in lymphoid tissues such as thymus, spleen, peripheral blood (PB) and lymph nodes (LN),as well as liver. We also show that DKO-hu-HSC mice allow high and persistent levels of HIV-1 infection in lymphoid organs and liver. Human CD4+ T cells are gradually depleted by HIV-1 in a dose-dependent manner, correlated with induction of inflammatory cytokines and lymphocyte infiltration in the liver. In addition, HIV-1 infection persisted in infected DKO-hu HSC mice for >20 weeks, with HIV-1 in lymphoid and liver tissues. Furthermore, HIV-1 or EBV infection induces human immune responses. Recently, we co-engrafted human hepatocytes and human immune system in the DKO mouse transplanted with human hepatocyte progenitor cells and CD34+ HSC cells (DKO-hu HSC/Hep mice). I propose to optimize the DKO-hu HSC/Hep mouse to increase human hepatocyte engraftment by selectively depleting murine hepatocytes and promoting human hepatocytes in the DKO-hu HSC/Hep mouse. We will also study how ethanol and HIV-1 coinfection affect HCV infection and liver pathogenesis in this model. The long-term goals of this project are to 1) develop a relevant mouse model to investigate the immuno- pathogenesis of HCV infection and HCV/HIV coinfection, 2) study how alcohol affects HIV or HCV infection and liver pathogenesis in vivo. Specifically, we will optimize the DKO-hu HSC/Hep model for studying HCV infection and immuno-pathogenesis. We will establish the effect of alcohol treatment on the infection and liver pathogenesis of HCV. We will also investigate how HIV co-infection affects HCV replication and pathogenesis. These studies will establish the foundation for future study and shed light on novel therapeutic strategies for controlling liver diseases associated with HIV and/or HCV infection. PUBLIC HEALTH RELEVANCE: The long-term goals of this project are to 1) develop a novel mouse model to investigate the immuno- pathogenesis of HCV infection and HCV/HIV coinfection, and 2) study how alcohol affects HIV or HCV infection and liver pathogenesis in vivo. We will establish the effect of alcohol treatment on the infection and liver pathogenesis of HCV. We will also investigate how HIV co-infection affects HCV replication and pathogenesis. These studies will establish the foundation for future study and shed light on novel therapeutic strategies for controlling liver diseases associated with HIV and/or HCV infection.