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

HIV合并感染和HCV诱导的体内肝纤维化

基本信息

批准号：
8584278
负责人：
Lishan Su
金额：
$ 37万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-12-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8584278
关键词：
Acquired Immunodeficiency Syndrome Address Affect Animal Model B-Lymphocytes Blood CCR5 gene Cell Culture Techniques Cell physiology Cells Chronic Coculture Techniques Development Engraftment Fibrosis Foundations Future Gene Expression Genes Genomics Goals HIV HIV Infections HIV-1 Hepatic Hepatic Fibrogenesis Hepatic Stellate Cell Hepatitis Hepatitis C Hepatitis C virus Hepatocyte Human Immune Immune response Immune system Immunologics In Vitro Infection Inflammation Inflammatory Response Kinetics Knockout Mice Light Liver Liver Cirrhosis Liver Fibrosis Liver diseases Lymphoid Measures Mediating Modeling Monitor Mus Natural Killer Cells Organ Pan Genus Pathogenesis Patients Play Regulatory T-Lymphocyte Reporting Role Stem cells T cell response T-Lymphocyte Testing Tissues Transfection Transgenes Transplantation Viral Virus Virus Replication immune function immunopathology improved in vivo liver cell proliferation liver inflammation metabolomics novel novel therapeutics prevent stellate cell suicidal viral RNA

项目摘要

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.

描述（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，但由于缺乏合适的动物模型，其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，支持所有淋巴器官中功能性人类免疫系统的发育。为了促进人类肝细胞共植入，我们在 DKO 小鼠中引入了肝脏特异性诱导自杀转基因（AFC8）。将人类血液和肝脏祖细胞共同移植到 AFC8 小鼠体内，可导致淋巴/肝脏器官（AFC8-hu 小鼠）中人类肝细胞和免疫细胞的发育。这些小鼠能够感染 HCV 和 HIV，支持抗病毒人类 T 细胞反应，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 复制来影响 HCV 诱发的肝脏疾病；加剧慢性肝脏炎症；并通过激活肝星状细胞加速肝纤维化。 AFC8-hu 模型非常适合阐明 HCV/HIV 协同作用在体内人肝纤维化中的机制。我们提出以下目标：1）将改进当前的 AFC8-hu 小鼠，以支持嵌合肝脏中的高级人类肝细胞。此外，还将测试 HCV gt 1a 和 2a 克隆，以确定它们的感染和发病动力学。 2) 研究HIV共感染如何加剧AFC8-hu小鼠中HCV诱导的肝纤维化。我们将定义 HIV 感染如何影响 HCV 感染、免疫发病机制、星状细胞激活和肝纤维化。此外，HCV感染对HIV-1复制和艾滋病进展的影响也将受到监测。 3) 我认为 HIV 合并感染会失调人类炎症和免疫反应，从而导致 HCV 相关的肝脏疾病。我们将定义关键的 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 AFC8-hu 小鼠的独特之处在于提供了可以解决这些重要问题的小动物模型。这些问题的答案将会对该领域产生非常重大的影响。