Extracellular vesicles as the vehicles for promoting liver injury induced by HIV and alcohol

项目摘要/摘要 肝病是艾滋病毒感染患者死亡的第二大原因，但作为一种 这一感染的组成部分需要进一步研究。艾滋病毒感染损害肝细胞，包括居民 巨噬细胞(即枯否细胞)和肝细胞。HIV引起的肝脏毒性因二次击中而增强， 包括酒精。饮酒通过增加病毒血症来增强艾滋病毒感染的病理特征， 抑制免疫反应，促进不坚持治疗，并导致艾滋病毒治疗不力 结果。此外，抗逆转录病毒疗法(ART)对大量服用的个体效果较差。 酒精和某些药物也会产生肝脏毒性，导致停止治疗。与此同时，它是 现在清楚的是，肝脏在HIV感染的发病机制中起着重要作用。有可能在艾滋病病毒中- 被感染的酒精滥用者，感染的传播和肝脏病理是细胞到细胞的结果 通过细胞外小泡(EV)进行通讯，包括凋亡小体(ABS)和含有病毒的外切体 核酸、miRNAs以及艾滋病毒和酒精修饰的宿主细胞货物，这些都会促进肝脏损伤。 此外，来自肝细胞的EV可以将炎症传播到其他器官。在这项研究中，我们假设 乙醇代谢通过EVS放大HIV触发的肝细胞和巨噬细胞之间的通讯， 从而促进肝脏炎症和纤维化。此外，这些EVS的肝外系统分布 可能会导致艾滋病毒的系统性传播和炎症向其他器官的传播。这一假设 将在以下三个具体目标中进行测试： 1.研究酒精对HIV诱导的肝细胞死亡的增强作用及大细胞外基质的作用 小泡(即凋亡小体)在巨噬细胞促进肝脏炎症中的作用。 2.明确酒精如何加速HIV诱导的肝细胞外切体的释放以及外切体的作用 肝细胞和巨噬细胞在肝脏炎症发展过程中的相互作用 3.阐明EVS在HIV感染和酒精摄入所致的肝损伤中的作用 活体 这项临床前研究将为未来的临床试验和翻译提供基础。此外， 通过发现潜在的肝损伤生物标志物，这些发现可以很容易地转化为临床实践。 在酗酒的人中伴随着艾滋病毒感染的进展。通过阻止电动汽车的释放，我们将寻求 预防肝病和全身性炎症的其他治疗方法。

PROJECT SUMMARY/ABSTRACT Liver disease is the second-leading cause of mortality in HIV-infected patients, but its significance as a component of this infection requires further study. HIV infection damages liver cells, including resident macrophages (i.e., Kupffer cells) and hepatocytes. HIV-induced hepatotoxicity is potentiated by second hits, including alcohol. Alcohol consumption enhances the pathological features of HIV infection by increasing viremia, suppressing immune responses, promoting non-adherence to treatment, and causing poor HIV treatment outcomes. In addition, antiretroviral therapy (ART) is less effective in individuals who consume large quantities of alcohol, and certain drugs also provide hepatotoxic effects, leading to treatment cessation. Meanwhile, it is now clear that the liver plays an important role in the pathogenesis of HIV infection. It is possible that in HIV- infected alcohol abusers, the dissemination of infection and liver pathology results from cell-to-cell communication via extracellular vesicles (EVs), including apoptotic bodies (ABs) and exosomes containing viral nucleic acids, miRNAs as well as HIV- and alcohol-modified host cell cargos, which promote liver injury. Moreover, EVs from liver cells can spread inflammation to other organs. In this study, we hypothesize that ethanol metabolism amplifies HIV-triggered communication between hepatocytes and macrophages via EVs, thereby promoting liver inflammation and fibrosis. Furthermore, extrahepatic systemic distribution of these EVs may contribute to the systemic spread of HIV and dissemination of inflammation to other organs. This hypothesis will be tested in the following three Specific Aims: 1. Examine potentiating effects of alcohol on HIV-induced hepatocyte death and the role of large extracellular vesicles (i.e., apoptotic bodies) in promoting liver inflammation by macrophages. 2. Define how alcohol accelerates HIV-induced exosome release from hepatocytes and the role of exosomes in cross-talk between hepatocytes and macrophages in the development of liver inflammation 3. Elucidate the contribution of EVs to liver injury caused by both HIV-infection and ethanol consumption in vivo This pre-clinical investigation will provide the foundation for future clinical trials and translation. Furthermore, these findings could be readily translated to clinical practice by discovering potential biomarkers of liver injury progression, which accompany HIV-infection in those who abuse alcohol. By blocking EV release, we will seek additional treatment modalities that prevent the development of liver disease and systemic inflammation.