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: 10091967
• 负责人: NATALIA ALEKSANDR OSNA
• 金额: $ 52.57万
• 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/10091967
• 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; Hepatic; 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; driving force; exosome; extracellular vesicles; hepatocyte injury; immune activation; in vivo; inhibitor/antagonist; liver development; liver inflammation; liver injury; macrophage; mortality; novel diagnostics; pathogen; potential biomarker; pre-clinical; prevent; systemic inflammatory response; tool; 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.

项目摘要/摘要 肝病是艾滋病毒感染患者死亡率的第二大原因，但其意义作为一种 这种感染的成分需要进一步研究。 HIV感染损害肝细胞，包括居民 巨噬细胞（即kupffer细胞）和肝细胞。艾滋病毒诱导的肝毒性被第二次命中增强 包括酒精。饮酒通过增加病毒血症，增强HIV感染的病理特征 抑制免疫反应，促进对治疗的不遵守，并导致HIV治疗不佳 结果。此外，抗逆转录病毒疗法（ART）在消耗大量的个体中的有效性较低 酒精和某些药物也提供肝毒性作用，导致治疗停止。同时，是 现在清楚地表明，肝脏在HIV感染的发病机理中起着重要作用。在艾滋病毒中可能 受感染的酒精滥用者，感染和肝脏病理的传播是由细胞到细胞引起的 通过细胞外囊泡（EV）进行通信，包括凋亡人物（ABS）和含有病毒的外泌体 核酸，miRNA以及HIV和酒精改性的宿主细胞cargos，可促进肝损伤。 此外，来自肝细胞的电动汽车会将炎症扩散到其他器官。在这项研究中，我们假设 乙醇代谢可以通过电动汽车与肝细胞和巨噬细胞之间的艾滋病毒触发的通信， 从而促进肝脏炎症和纤维化。此外，这些电动汽车的肝外系统分布 可能有助于艾滋病毒的全身传播和炎症传播到其他器官。这个假设 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和大细胞外的作用 在巨噬细胞促进肝脏炎症方面，囊泡（即凋亡体）。 2。定义酒精如何加速艾滋病毒引起的外泌体从肝细胞释放和外泌体的作用 在肝脏炎症发展中肝细胞和巨噬细胞之间的串扰 3。阐明了由HIV感染和乙醇消耗引起的电动汽车对肝损伤的贡献 体内 这项临床前研究将为将来的临床试验和翻译提供基础。此外， 这些发现可以通过发现肝损伤的潜在生物标志物很容易地转化为临床实践 在滥用酒精的人中伴随着艾滋病毒感染的进展。通过阻止EV发布，我们将寻求 防止肝病和全身性炎症发展的其他治疗方式。