HIV co-infection and HCV-induced liver fibrosis in vivo

描述(申请人提供)：丙型肝炎病毒(丙型肝炎病毒)感染和HIV混合感染协同作用促进肝纤维化和肝硬变，但由于缺乏合适的动物模型，潜在的致病机制仍不清楚。BalbC rag2/？C双基因敲除(DKO)小鼠缺乏T、B和NK细胞，并支持所有淋巴器官中功能正常的人类免疫系统的发育。为了促进人肝细胞共移植，我们在DKO小鼠体内引入了肝脏特异性诱导性自杀转基因(AFC8)。人血和肝祖细胞在AFC8小鼠体内的共移植可使人肝细胞和淋巴器官/肝脏器官中的免疫细胞同时发育(AFC8-Hu小鼠)。这些小鼠对丙型肝炎病毒和艾滋病毒感染是允许的，支持抗病毒的人类T细胞反应，并发展为人类肝脏免疫病理学(炎症、肝炎和纤维化)。我推测，HIV合并感染可能通过促进丙型肝炎病毒复制，通过增加慢性肝脏炎症，以及通过激活肝星状细胞来加速肝纤维化，从而影响丙型肝炎病毒引起的肝病。AFC8-Hu模型非常适合于阐明体内人肝纤维化中丙型肝炎病毒/艾滋病病毒协同作用的机制。我们提出了以下目标：1)对现有的AFC8-HU小鼠进行改良，以支持嵌合肝脏中较高的人肝细胞。此外，将对丙型肝炎病毒GT 1a和2a克隆进行测试，以确定 它们的感染和发病动力学。2)研究HIV混合感染如何加重丙型肝炎病毒诱导的AFC8-Hu小鼠肝纤维化。我们将定义艾滋病毒感染如何影响丙型肝炎病毒感染、免疫发病机制、星形细胞激活和肝纤维化。此外，还将监测丙型肝炎病毒感染对HIV-1复制和艾滋病进展的影响。3)我认为HIV合并感染会扰乱人类的炎症和免疫反应，从而导致丙型肝炎病毒相关的肝病。我们将确定关键的HIV靶细胞PDC和Treg在体外和体内促进丙型肝炎病毒诱导的肝星状细胞激活和纤维化的作用。新型AFC8-HU小鼠的独特之处在于提供了一个可以解决这些重要问题的小动物模型。这些问题的答案将对该领域产生非常重大的影响。

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infection and HIV coinfection act synergistically to promote hepatic fibrosis and cirrhosis, but the underlying pathogenic mechanisms remain unclear due to a lack of appropriate animal models. The BalbC rag2/?C double knockout (DKO) mouse lacks T, B and NK cells and supports development of a functional human immune system in all lymphoid organs. To promote human liver cell co-engraftment, we introduced a liver-specific inducible suicidal transgene (AFC8) in the DKO mouse. Co-transplantation of human blood and liver progenitor cells in AFC8 mice leads to development of both human liver cells and immune cells in lymphoid/liver organs (AFC8-hu mice). These mice are permissive for HCV as well as HIV infection, support anti-viral human T cell responses, and develop human liver immunopathology (inflammation, hepatitis and fibrosis). I postulate that HIV co-infection may affect HCV-induced liver diseases by enhancing HCV replication; by elevating chronic hepatic inflammation; and by activating hepatic stellate cells to accelerate liver fibrosis. The AFC8-hu model is well suited for elucidating the mechanism underlying HCV/HIV synergy in human hepatic fibrosis in vivo. We propose the following aims: 1) The current AFC8-hu mouse will be improved to support higher human hepatocytes in the chimeric liver. In addition, HCV gt 1a and 2a clones will be tested to establish their infection and pathogenesis kinetics. 2) To study how HIV co-infection exacerbates HCV-induced liver fibrosis in AFC8-hu mice. We will define how HIV infection influences HCV infection, immunopathogenesis, stellate cell activation and liver fibrosis. In addition, the effectof HCV infection on HIV-1 replication and AIDS progression will also be monitored. 3) I propose that HIV coinfection dysregulates human inflammatory and immune responses to contribute to HCV-associated liver diseases. We will define the role of key HIV target cells pDC and Treg that promote HCV-induced liver stellate cell activation and fibrosis in vitro and in vivo. The novel AFC8-hu mouse is unique in providing a small animal model in which these important questions can be addressed. The answers to these questions will have a very significant impact on the field.