Cooperative mechanisms of HIV-enhanced liver fibrogenesis in HBV Coinfection

项目摘要/摘要 全球约有4000万人感染艾滋病毒，其中约10%患有慢性病 乙肝病毒(乙肝)合并感染。慢性乙肝进展为肝硬变、终末期肝 与慢性乙肝相比，HIV合并感染会加速疾病或肝细胞癌的发生 单一感染。包括恩替卡韦和替诺福韦在内的核(T)化物类似物(Nas)目前 被批准用于治疗慢性乙肝病毒感染。在艾滋病毒合并感染中，尽管有乙肝病毒 与Nas抑制相比，仍有证据表明更严重的肝损伤和纤维化。 NA抑制的HBV单感染。然而，艾滋病毒增加的机制 乙肝病毒复制和由乙肝病毒引起的肝纤维化尚未得到很好的描述。其中一个主要的 HIV-HBV共感染研究的障碍在于缺乏强大的动物模型或共培养模型。 我们在丙型肝炎病毒与艾滋病病毒混合感染中HIV引起的肝纤维化的研究方面有丰富的经验。 并将这一经验运用到艾滋病毒和乙肝病毒共同感染的相关模型中。vbl.使用 HIV/HBV单培养和新的Transwell和椭球共培养模型(最多3行) 在我们实验室开发的，我们发现艾滋病毒增加了乙肝病毒的复制，乙肝病毒cccDNA 表达，并增强乙肝病毒诱导的肝纤维化相关基因的表达 感染NTCP-HepG2和Lx2 HSC细胞。我们发现，乙肝病毒和艾滋病病毒的感染 诱导细胞因子紊乱，这可能导致纤维化。另外，我们发现 HIV促进丙酮酸的产生，进而促进肝纤维化。我们假设 HIV通过(1)肝纤维化原改变协同促进乙肝病毒相关性肝纤维化 细胞因子分泌和(2)丙酮酸状态的变化。为了评估这些假设，我们将 使用体外单一培养、Transwell和球体共培养模型并进行验证 体内人源化小鼠HIV/HBV共感染模型的肝脏和血液中的研究结果。这些 目标是可行的，有机械基础的，极有可能产生以下结果： 澄清艾滋病毒-乙肝病毒-宿主的相互作用。他们还可能产生一系列新的目标 用于开发旨在增强乙肝功能治疗和预防的治疗方法 艾滋病毒加速了乙肝肝病的进展。

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.