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

在发达国家，肝病目前是导致非艾滋病发病率和死亡率的最常见原因 在感染艾滋病毒的人中。事实上，非酒精性脂肪性肝病(NAFLD)在艾滋病毒期间更为普遍 与未感染人群相比，30-40%的艾滋病毒感染者中会发生感染。关键是， 脂肪肝正日益成为非酒精性脂肪性肝炎(NASH)的先兆， 可进一步发展为肝硬变和肝功能衰竭。进展为NAFLD和脂肪性肝炎 多因素，包括代谢变化、与TLR刺激和氧化相关的细胞因子释放 压力。关于艾滋病毒感染，肝病的确切驱动因素和机制还没有很好的定义。 这项建议将利用恒河猴和体外人类细胞培养中的SIV致病病毒感染 描述在SIV/HIV感染过程中导致肝病的早期介质。我们之前的研究评估 SIV感染猕猴和SIV感染手推车治疗猕猴的肝脏(尸检评估)被鉴定为增加 两组大鼠肝脏细菌16S DNA水平。重要的是，这项研究的一个意想不到的发现 是受感染猕猴肝脏中分枝杆菌16S DNA的浓缩，我们随后 鉴定为污垢分枝杆菌，一种共生或潜在的机会性病原体。这些数据也是 正如已发表的发现，导致了细菌和细菌移位的假说 进入肝脏的产物(包括与分枝杆菌相关的生物失调)是肝脏的关键介质。 在CART治疗的HIV/SIV感染期间的炎症，并可启动早期事件， 引发脂肪肝。这一假设将通过三个具体的目标来检验，前两个目标 评估SIV感染-CART治疗后肝脏、淋巴结和血液中免疫和微生物群的变化 猕猴。AIM 3将评估观察到的人类巨噬细胞或 肝细胞在HIV、CART和细菌/PAMPS暴露后的体外实验。我们的目标是 细菌易位和微生物群失调在HIV/SIV相关肝脏中的作用 炎症，特别是分枝杆菌。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，包括 先前的研究评估了SIV感染和CART治疗期间的肝脏炎症。此外，该团队 由俄勒冈州国家灵长类研究中心的Burwitz、Sacha和Smedley博士组成，他们拥有 成功开展上述实验所需的专业知识。总而言之，这些方法将 允许我们对艾滋病毒/SIV病毒、CART药物和药物的确切贡献进行机械评估 肠道来源的微生物在肝脏炎症中的作用以及确定这些介质的潜在协同作用 当在猕猴体内或体外结合时。我们的长期目标是确定一种免疫治疗策略，以 降低HIV感染者和接受CART治疗的人的肝病发病率和/或严重程度。

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.