Mediators of fatty liver disease during HIV/SIV and cART treatment

HIV/SIV 和 cART 治疗期间脂肪肝疾病的介质

• 批准号: 10089216
• 负责人: Donald L Sodora
• 金额: $ 87.94万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-19 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10089216
• 关键词: Acute; Address; Animals; Antibiotics; Autopsy; Bacteria; Bacterial Translocation; Blood; Cardiovascular Diseases; Cell Culture Techniques; Chronic Phase; Cirrhosis; DNA; Data; Developed Countries; Diabetes Mellitus; Disease; Event; Exposure to; Fatty Liver; Genus Mycobacterium; Goals; HIV; HIV Infections; HIV Seronegativity; HIV antiretroviral; Hepatocyte; Human; Hypertension; Immune; Immunologics; Immunotherapeutic agent; Immunotherapy; In Vitro; Incidence; Individual; Infection; Infiltration; Inflammation; Inflammatory; Kupffer Cells; Laboratories; Life Expectancy; Liver; Liver Failure; Liver diseases; Macaca; Macaca mulatta; Mediating; Mediator of activation protein; Metabolic; Microbe; Morbidity - disease rate; Mycobacterium smegmatis; Oregon; Oxidative Stress; Pathogenesis; Pathogenicity; Patients; Pharmaceutical Preparations; Population; Primates; Publishing; Research; Role; SIV; Severities; Steatohepatitis; Testing; Virus; antiretroviral therapy; bacteriome; comorbidity; cytokine; dysbiosis; experience; experimental study; fecal microbiome; liver inflammation; lymph nodes; macrophage; microbial; microbiome; mortality; mycobacterial; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; nonhuman primate; opportunistic pathogen; pathogen; prevent; sex; transcriptomics

Liver disease is currently the most common cause of non-AIDS morbidity and mortality in developed countries amongst HIV infected people. Indeed, non-alcoholic fatty liver disease (NAFLD) is more prevalent during HIV infection compared to the uninfected population occurring in 30-40% of HIV-infected individuals. Critically, fatty liver disease is becoming an increasingly recognized precursor to non-alcoholic steatohepatitis (NASH), which can further develop into cirrhosis and liver failure. Progression toward NAFLD and steatohepatitis is multifactorial, and includes metabolic changes, cytokine release associated with TLR stimulation and oxidative stress. With regards to HIV infection, the precise drivers and mechanisms of liver disease are not well defined. This proposal will utilize the pathogenic SIV infection of rhesus macaques and in vitro human cell cultures to delineate the early mediators that drive liver disease during SIV/HIV infection. Our previous study assessing livers from SIV-infected and SIV-infected-cART-treated macaques (assessed at necropsy) identified increased levels of bacterial 16s DNA in the livers of both groups. Importantly, an unexpected finding from this study was the enrichment of Mycobacterial 16s DNA in the liver of infected macaques, which we have subsequently identified as Mycobacteria smegmatis, a commensal or potentially opportunistic pathogen. These data, as well as published findings, have led to the hypothesis that translocation of bacteria and bacterial products to the liver (including Mycobacteria-associated dysbiosis) are key mediators of liver inflammation during cART-treated HIV/SIV-infection and can initiate the early events that trigger fatty liver disease. This hypothesis will be tested through three specific aims the first two Aims assess immune and microbiome changes within the liver, lymph node and blood in SIV-infected-cART-treated macaques. Aim 3 will evaluate the mechanisms underlying changes observed in human macrophages or hepatocytes utilizing in vitro experiments following exposure to HIV, cART and bacteria/PAMPs. Our goal is to delineate the role of bacterial translocation and microbiome dysbiosis in HIV/SIV-associated liver inflammation, with particular focus on mycobacteria. To undertake these aims, this study will be led by Dr. Sodora, who has 18 years of experience evaluating immune inflammation during HIV/SIV disease including previous studies assessing liver inflammation during SIV-infection and cART-treatment. In addition, the team consists of Drs. Burwitz, Sacha and Smedley at the Oregon National Primate Research Center who have the necessary expertise to successfully undertake the outlined experiments. Collectively, these approaches will allow us to undertake a mechanistic assessment of the precise contributions of HIV/SIV virus, cART drugs and gut-derived microbes in liver inflammation as well as identify potential synergistic effects of these mediators when combined in a macaque or in vitro. Our long-term goal is to identify an immune therapeutic strategy to reduce incidence and/or severity of liver disease in HIV-infected and cART-treated individuals.

肝病是目前发达国家非艾滋病发病和死亡的最常见原因 艾滋病病毒感染者中。事实上，非酒精性脂肪肝（NAFLD）在艾滋病毒感染期间更普遍。 与未感染人群相比，30%-40%的HIV感染者发生感染。关键是， 脂肪肝疾病正日益成为非酒精性脂肪性肝炎（NASH）的前兆， 可进一步发展为肝硬化和肝功能衰竭。NAFLD和脂肪性肝炎的进展是 多因素，包括代谢变化，与TLR刺激相关的细胞因子释放和氧化 应力关于艾滋病毒感染，肝脏疾病的确切驱动因素和机制尚未明确。 该提案将利用恒河猴的致病性SIV感染和体外人类细胞培养， 描述SIV/HIV感染期间驱动肝病的早期介质。我们之前的研究评估了 SIV感染和SIV感染cART治疗的猕猴的肝脏（尸检时评估）鉴定为增加 两组肝脏中细菌16 s DNA的水平。重要的是，这项研究的一个意外发现 是结核分枝杆菌16 s DNA在感染猕猴的肝脏中富集，我们随后 鉴定为耻垢分枝杆菌，一种寄生性或潜在的机会性病原体。这些数据也 正如已发表的研究结果，已经导致假设，细菌和细菌的易位， 产品的肝脏（包括分枝杆菌相关的生态失调）是肝脏的关键介质 在cART治疗的HIV/SIV感染过程中炎症，并可启动早期事件， 引发脂肪肝这一假设将通过三个具体目标进行检验，前两个目标 评估SIV感染的cART治疗患者肝脏、淋巴结和血液中的免疫和微生物组变化 猕猴目的3将评估在人巨噬细胞或 在暴露于HIV、cART和细菌/PAMP后，利用体外实验对肝细胞进行研究。我们的目标是 描述HIV/SIV相关肝脏中细菌移位和微生物组生态失调的作用 炎症，特别关注分枝杆菌。为了实现这些目标，这项研究将由Dr. Sodora有18年评估HIV/SIV疾病期间免疫炎症的经验， 先前评估SIV感染和cART治疗期间肝脏炎症的研究。此外，该团队 由俄勒冈州国家灵长类动物研究中心的Burwitz、Sacha和Smedley博士组成， 成功进行上述实验所需的专业知识。总的来说，这些方法将 使我们能够对HIV/SIV病毒、cART药物和 肠道来源的微生物在肝脏炎症以及确定这些介质的潜在协同作用 当在猕猴中或体外组合时。我们的长期目标是确定一种免疫治疗策略， 降低HIV感染和cART治疗个体的肝病发病率和/或严重程度。