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

细胞外囊泡作为促进 HIV 和酒精引起的肝损伤的载体

• 批准号: 10355439
• 负责人: NATALIA ALEKSANDR OSNA
• 金额: $ 51.35万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-10 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10355439
• 关键词: Affect; Alcohol abuse; Alcohol consumption; Alcohols; Apoptosis; Apoptotic; Blood Circulation; Cell Communication; Cells; Cessation of life; Characteristics; Chronic Hepatitis; Clinical Trials; Communication; Consumption; Development; Ethanol; Ethanol Metabolism; Exposure to; Extrahepatic; Foundations; Future; Goals; HIV; HIV Infections; Hepatitis B; Hepatitis C; Hepatocyte; Hepatotoxicity; Immune; Immune response; Individual; Infection; Inflammation; Inflammatory; Kupffer Cells; Liver; Liver Fibrosis; Liver diseases; Mediating; MicroRNAs; Modality; Nucleic Acids; Organ; Pathogenesis; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Play; Production; Proteins; RNA; Role; Scheme; Stress; Supporting Cell; Testing; Toxic effect; Transaminases; Translating; Translations; Treatment outcome; Viral; Viremia; Virus; Withholding Treatment; alcohol abuser; alcohol effect; antiretroviral therapy; clinical investigation; clinical practice; clinical translation; cytokine; diagnostic tool; driving force; end stage liver disease; exosome; extracellular vesicles; hepatocyte injury; immune activation; in vivo; inhibitor; liver development; liver inflammation; liver injury; macrophage; mortality; novel diagnostics; pathogen; potential biomarker; pre-clinical; prevent; systemic inflammatory response; vesicular release

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.

项目总结/摘要 肝脏疾病是艾滋病毒感染者死亡的第二大原因，但其作为一种重要的疾病， 这种感染需要进一步研究。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诱导的肝毒性通过第二次打击而增强， 包括酒精。饮酒通过增加病毒血症， 抑制免疫反应，促进不遵守治疗，并导致艾滋病毒治疗效果不佳 结果。此外，抗逆转录病毒疗法（ART）在大量服用的个体中效果较差。 酒精和某些药物也提供肝毒性作用，导致治疗停止。同时也是 目前已明确肝脏在HIV感染的发病机制中起着重要作用。有可能在艾滋病病毒- 受感染的酒精滥用者，感染的传播和肝脏病理结果从细胞到细胞 通过细胞外囊泡（EV）进行通讯，包括凋亡小体（AB）和含有病毒的外来体 核酸、miRNA以及HIV和酒精修饰的宿主细胞货物，其促进肝损伤。 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EV放大了肝细胞和巨噬细胞之间的HIV触发的通信， 从而促进肝脏炎症和纤维化。此外，这些EV的肝外全身分布 可能导致HIV的全身传播和炎症扩散到其他器官。这一假设 将在以下三个具体目标中进行测试： 1.检查酒精对HIV诱导的肝细胞死亡的增强作用以及大细胞外基质的作用。 囊泡（即，凋亡小体）通过巨噬细胞促进肝脏炎症。 2.定义酒精如何加速HIV诱导的外泌体从肝细胞释放以及外泌体的作用 在肝脏炎症发展过程中肝细胞和巨噬细胞之间的相互作用 3.阐明电动汽车对艾滋病毒感染和乙醇消耗引起的肝损伤的贡献， 体内 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，委员会还认为， 通过发现肝损伤的潜在生物标志物，这些发现可以很容易地转化为临床实践 酗酒者伴随艾滋病毒感染而出现进展。通过阻止EV释放，我们将寻求 预防肝病和全身性炎症发展的其他治疗方式。