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共同感染协同作用，促进肝纤维化和肝硬化，但由于缺乏适当的动物模型，其潜在的致病机制尚不清楚。BalbC rag2/？C双敲除（DKO）小鼠缺乏T、B和NK细胞，并支持在所有淋巴器官中功能性人类免疫系统的发展。为了促进人肝细胞共植入，我们在DKO小鼠中引入了肝脏特异性诱导自杀转基因（AFC8）。人血祖细胞和肝祖细胞在AFC8小鼠体内共移植，可导致人肝细胞和淋巴/肝器官免疫细胞的发育（AFC8-hu小鼠）。这些小鼠允许HCV和HIV感染，支持抗病毒人类T细胞反应，并发生人类肝脏免疫病理（炎症、肝炎和纤维化）。我推测HIV合并感染可能通过增强HCV复制而影响HCV诱导的肝脏疾病；通过提高慢性肝脏炎症；通过激活肝星状细胞加速肝纤维化。AFC8-hu模型非常适合于阐明HCV/HIV协同作用在人体内肝纤维化中的机制。我们提出以下目标：1)改进现有的AFC8-hu小鼠，使其在嵌合肝脏中支持更多的人肝细胞。此外，将对HCV gt 1a和2a克隆进行检测以确定

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.