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: 10426106
• 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 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10426106
• 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 Fibrogenesis; Hepatic Stellate Cell; Hepatitis B Virus; Hepatitis C co-infection; Hepatitis C virus; Hepatocyte; Human; In Vitro; Infection; 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; end stage liver disease; endoplasmic reticulum stress; entecavir; experience; fibrogenesis; humanized mouse; improved; in vivo; in vivo Model; insight; liver inflammation; 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.

项目总结/摘要 全世界约有4000万人感染艾滋病毒，其中约10%的人患有慢性 B型肝炎病毒（HBV）合并感染。慢性HBV向肝硬化、终末期肝病的进展 与慢性HBV相比，HIV合并感染加速了肝细胞癌的发生 单一感染包括恩替卡韦和替诺福韦在内的核苷（酸）类似物（NA）目前被 用于治疗慢性HBV感染。在HIV合并感染中，尽管HBV 与NAs抑制相比，仍有证据表明肝损伤和纤维化更严重。 NA抑制的HBV单一感染。然而，艾滋病毒增加的机制 HBV复制和HBV诱导的肝纤维化尚未得到很好的表征。的一个主要 HIV-HBV共感染研究的障碍是缺乏可靠的动物或共培养模型。 我们在HCV-HIV合并感染中HIV诱导的肝纤维化的研究方面有着丰富的经验 并将这一经验应用于HIV-HBV合并感染的相关模型中。使用 HIV/HBV单培养和新型transwell和球状体共培养模型（最多3个细胞系） 在我们的实验室开发的，我们已经发现，艾滋病毒增加HBV复制，HBV cccDNA 水平，并增强HBV诱导的肝纤维化相关基因在HBV HepAD 38，HBV- 感染NTCP-HepG 2和LX 2 HSC细胞。我们发现HBV和HIV感染 诱导细胞因子紊乱，可能导致纤维化。另外，我们发现， HIV促进丙酮酸的产生，这反过来又促进肝纤维化。我们假设 HIV通过以下方式协同促进HBV相关的肝纤维化：（1）促纤维化蛋白的改变 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 使用体外单培养、transwell和球状体共培养模型并验证这些 在来自体内人源化小鼠HIV/HBV共感染模型的肝脏和血液中的发现。这些 目标是可行的，有机械基础的，并且很有可能产生结果， 阐明HIV-HBV-宿主相互作用。它们还可能产生一系列新的目标 用于开发旨在增强HBV功能性治愈和预防的治疗方法 HIV加速HBV肝病进展。

项目成果

Differentially expressed immune response genes in COVID-19 patients based on disease severity.

根据疾病严重程度，COVID-19 患者中差异表达的免疫反应基因

• DOI: 10.18632/aging.202877
• 发表时间: 2021-03-29
• 期刊: Aging
• 作者: Li S;Duan X;Li Y;Li M;Gao Y;Li T;Li S;Tan L;Shao T;Jeyarajan AJ;Chen L;Han M;Lin W;Li X
• 通讯作者: Li X

Hsa_circ_0007321 regulates Zika virus replication through miR-492/NFKBID/NF-κB signaling pathway.

• DOI: 10.1128/jvi.01232-23
• 发表时间: 2023-12-21
• 期刊: Journal of virology
• 影响因子: 5.4

Vaccination increased host antiviral gene expression and reduced COVID-19 severity during the Omicron variant outbreak in Fuyang City, China.

• DOI: 10.1016/j.intimp.2023.110333
• 发表时间: 2023-07
• 期刊: INTERNATIONAL IMMUNOPHARMACOLOGY
• 影响因子: 5.6
• 作者: Li, Shasha;Duan, Xiaoqiong;Jiang, Ning;Jeyarajan, Andre J.;Warner, Charlotte A.;Li, Yujia;Xu, Min;Li, Xiuyong;Tan, Lin;Li, Ming;Shao, Tuo;Li, Shilin;Chen, Limin;Gao, Yufeng;Han, Mingfeng;Lin, Wenyu
• 通讯作者: Lin, Wenyu

Hepatitis B viral replication markers and hepatic fibrosis in untreated chronic hepatitis B virus infection with and without HIV coinfection in Zambia.

赞比亚未经治疗的慢性乙型肝炎病毒感染伴或不伴艾滋病毒合并感染的乙型肝炎病毒复制标志物和肝纤维化。

• DOI: 10.1097/qad.0000000000003659
• 发表时间: 2023
• 期刊: AIDS (London, England)
• 作者: Muula,GuyK;Bosomprah,Samuel;Sinkala,Edford;Nsokolo,Bright;Musonda,Taonga;Hamusonde,Kalongo;Bhattacharya,Debika;Lauer,Georg;Chung,RaymondT;Mulenga,LloydB;Wandeler,Gilles;Vinikoor,MichaelJ
• 通讯作者: Vinikoor,MichaelJ