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

描述（由申请人提供）：研究HIV/HCV合并感染和肝脏疾病的新型人源化小鼠模型HIV+个体饮酒与病毒合并感染和肝脏疾病的易感性增加有关。HIV-1和HCV（丙型肝炎病毒）合并感染，由于共享传播途径而高度流行，与HCV感染患者的肝脏疾病加速进展相关。目前迫切需要一种允许HCV和/或HIV复制和发病的小鼠模型来研究乙醇和HIV共感染对HCV感染和肝脏发病的影响。Rag2-C双敲除（DKO）小鼠缺乏T/B和NK细胞，并允许与人类造血干细胞（DKO-hu HSC小鼠）发展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淋巴组织中，如胸腺、脾脏、外周血（PB）和淋巴结（LN），以及肝脏。我们还表明，DKO-hu-HSC小鼠在淋巴器官和肝脏中允许高水平和持续水平的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，这与肝脏中炎症细胞因子和淋巴细胞浸润的诱导有关。此外，受感染的DKO-hu HSC小鼠的HIV-1感染持续了100 - 20周，在淋巴组织和肝脏组织中存在HIV-1。此外，HIV-1或EBV感染诱导人类免疫反应。最近，我们将人肝细胞和人免疫系统共同移植到人肝细胞祖细胞和CD34+ HSC细胞移植的DKO小鼠（DKO-hu HSC/Hep小鼠）中。我建议通过选择性消耗小鼠肝细胞和促进DKO-hu HSC/Hep小鼠的人肝细胞来优化DKO-hu HSC/Hep小鼠，以增加人肝细胞的植入。我们还将研究乙醇和HIV-1共同感染如何影响HCV感染和肝脏发病机制。本项目的长期目标是：1)建立相关的小鼠模型，研究HCV感染和HCV/HIV合并感染的免疫发病机制；2)研究酒精对体内HIV或HCV感染和肝脏发病机制的影响。具体而言，我们将优化DKO-hu HSC/Hep模型，用于研究HCV感染和免疫发病机制。我们将建立酒精治疗对HCV感染和肝脏发病机制的影响。我们还将研究HIV合并感染如何影响HCV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HIV和/或HCV感染相关的肝脏疾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.