Cooperative mechanisms of HIV-enhanced liver fibrogenesis in HBV Coinfection

HBV 合并感染中 HIV 增强肝纤维化的协同机制

• 批准号: 10082973
• 负责人: RAYMOND T CHUNG
• 金额: $ 70.91万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10082973
• 关键词: Address; Animal Model; Animals; Antiviral Agents; Antiviral Therapy; Biological Models; Blood; CCR5 gene; CXCR4 gene; Cell Line; Cells; Chronic Hepatitis B; Circular DNA; Cirrhosis; Coculture Techniques; DNA biosynthesis; Disease Progression; Down-Regulation; Fibrosis; Gene Expression; Genetic Transcription; HBV Liver Disease; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; HIV/HCV; HepG2; Hepatic; Hepatic Fibrogenesis; Hepatic Stellate Cell; Hepatitis B Virus; Hepatitis C co-infection; Hepatitis C virus; Hepatocyte; Human; In Vitro; Infection; Inflammation; Interferon-alpha; Interruption; Laboratories; Liver; Liver Cirrhosis; Liver Fibrosis; Liver diseases; Malignant neoplasm of liver; Mediator of activation protein; Metabolic; Modeling; PPAR alpha; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Peroxisome Proliferator-Activated Receptors; Persons; Primary carcinoma of the liver cells; Production; Proteins; Pyruvate; Pyruvate Kinase; Pyruvate Metabolism Pathway; Reactive Oxygen Species; Serum; Signal Transduction; Taurocholate Sodium; Tenofovir; Testing; Viral; Virus Diseases; Virus Replication; analog; base; chemokine receptor; co-infection; cytokine; endoplasmic reticulum stress; entecavir; experience; fibrogenesis; humanized mouse; improved; in vivo; in vivo Model; insight; liver injury; macrophage; mitochondrial metabolism; mortality; mouse model; novel; novel strategies; nuclease; polypeptide; prevent; response; therapy design; therapy development; treatment comparison; virus host interaction; vpr Gene Products

Project Summary/Abstract HIV infects about 40 million people worldwide, among whom approximately 10% harbor chronic hepatitis B virus (HBV) co-infection. The progression of chronic HBV to cirrhosis, end-stage liver disease, or hepatocellular carcinoma is accelerated in HIV coinfection compared to chronic HBV monoinfection. Nucleos(t)ide analogues (NAs) including entecavir and tenofovir are currently approved for the treatment of chronic HBV infection. In HIV coinfection, despite HBV suppression with NAs, there is still evidence for more severe liver injury and fibrosis compared with NA-suppressed HBV monoinfection. However, the mechanisms by which HIV increases HBV replication and HBV-induced liver fibrosis are not well characterized. One of the major obstacles in HIV-HBV coinfection study has been the lack of a robust animal or co-culture model. We have extensive experience in the study of HIV-induced liver fibrosis in HCV-HIV coinfection and have parlayed this experience into relevant models for HIV-HBV co-infection. Using HIV/HBV mono-culture and novel transwell and spheroid co-culture models (up to 3 lines) developed in our laboratory, we have found that HIV increases HBV replication, HBV cccDNA levels, and enhances HBV-induced fibrosis-related gene expression in HBV HepAD38, HBV- infected NTCP-HepG2 and LX2 HSC cells. We have found that HBV and HIV infection each induce cytokine disturbances that could contribute to fibrosis. Separately, we have found that HIV enhances pyruvate production, which in turn promotes hepatic fibrosis. We hypothesize that HIV cooperatively promotes HBV-related liver fibrosis through (1) alterations in profibrogenic cytokine secretion and (2) changes in pyruvate status. To evaluate these hypotheses, we will use in vitro mono-culture, and transwell and spheroid co-culture models and verify these findings in liver and blood from in vivo humanized mice HIV/HBV coinfection models. These Aims are feasible, mechanistically grounded, and highly likely to yield results that will lead to clarification of HIV-HBV-host interactions. They are also likely to yield an array of new targets for the development of treatments designed to enhance HBV functional cure and preventing HIV-accelerated HBV liver disease progression.

项目摘要/摘要 艾滋病毒在全球大约感染了约4000万人，其中约有10％的港口慢性病 肝炎病毒（HBV）共感染。慢性HBV向肝硬化，终末期肝脏的进展 与慢性HBV相比，疾病或肝细胞癌在HIV共感染中加速 单感染。核（T）IDE类似物（NAS）包括Entecavir和Tenofovir包括 批准治疗慢性HBV感染。在HIV共感染中，尽管HBV NAS抑制，仍然有证据表明肝损伤更严重和纤维化。 与NA抑制的HBV单感染。但是，艾滋病毒增加的机制 HBV复制和HBV诱导的肝纤维化未充分表征。专业之一 HIV-HBV共感染研究中的障碍是缺乏强大的动物或共培养模型。 我们在HCV-HIV共感染中对HIV诱导的肝纤维化的研究具有丰富的经验 并将这种经验分解为HIV-HBV共感染的相关模型。使用 艾滋病毒/HBV单文化以及新型Transwell和Spheroid共培养模型（最多3行） 在我们的实验室中开发的，我们发现HIV增加了HBV复制，HBV CCCDNA 水平，并增强HBV诱导的HBV HEPAD38，HBV-的纤维化相关基因表达 感染的NTCP-HEPG2和LX2 HSC细胞。我们发现HBV和HIV感染每个 诱导可能导致纤维化的细胞因子障碍。单独，我们发现 HIV增强了丙酮酸的产生，从而促进肝纤维化。我们假设这一点 HIV通过（1）改变与纤维化的改变促进与HBV相关的肝纤维化 细胞因子分泌和（2）丙酮酸状况的变化。为了评估这些假设，我们将 使用体外单培养以及Transwell和Spheroid共培养模型并验证这些模型 肝脏中的肝脏和血液中的发现，来自体内人性化小鼠HIV/HBV共感染模型。这些 目的是可行的，机械基础的，并且很有可能产生的结果将导致 澄清HIV-HBV-host相互作用。他们也可能产生一系列新目标 为了开发旨在增强HBV功能治愈和防止HBV的治疗方法 HIV加速HBV​​肝病进展。