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

描述（由申请人提供）：丙型肝炎病毒（HCV）感染和HIV合并感染协同作用，促进肝纤维化和肝硬化，但由于缺乏适当的动物模型，潜在的致病机制仍不清楚。BalbC Rag2/？C双敲除（DKO）小鼠缺乏T、B和NK细胞，并支持所有淋巴器官中功能性人免疫系统的发育。为了促进人肝细胞共移植，我们在DKO小鼠中引入了肝脏特异性诱导自杀转基因（AFC 8）。在AFC 8小鼠中共移植人血和肝祖细胞导致淋巴/肝器官（AFC 8-hu小鼠）中人肝细胞和免疫细胞的发育。这些小鼠允许HCV和HIV感染，支持抗病毒人类T细胞应答，并发展人类肝脏免疫病理学（炎症，肝炎和纤维化）。我推测HIV合并感染可能通过增强HCV复制、升高慢性肝脏炎症和激活肝星状细胞加速肝纤维化来影响HCV诱导的肝脏疾病。AFC 8-hu模型非常适合于阐明体内HCV/HIV协同作用在人肝纤维化中的机制。我们提出了以下目标：1）目前的AFC 8-hu小鼠将被改进以支持嵌合肝脏中的更高的人肝细胞。此外，还将检测HCV gt 1a和2a克隆， 它们的感染和致病动力学。2)研究HIV合并感染如何加重HCV诱导的AFC 8-hu小鼠肝纤维化。我们将明确HIV感染如何影响HCV感染、免疫发病机制、星状细胞活化和肝纤维化。此外，还将监测HCV感染对HIV-1复制和AIDS进展的影响。3)我认为HIV合并感染导致人类炎症和免疫反应失调，从而导致HCV相关的肝脏疾病。我们将确定关键的HIV靶细胞pDC和Treg在体外和体内促进HCV诱导的肝星状细胞活化和纤维化的作用。新型AFC 8-hu小鼠在提供可以解决这些重要问题的小动物模型方面是独一无二的。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.