RESPIRATORY BURST, CYTOKINES AND HIV IN ALCOHOLICS

酗酒者的呼吸爆发、细胞因子和 HIV

• 批准号: 2516830
• 负责人: ABRAHAM P. BAUTISTA
• 金额: $ 18.03万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2516830
• 关键词: AIDS; HIV envelope protein gp120; HIV infections; Kupffer's cell; NAD(P)H oxidoreductase; alcoholic liver cirrhosis; alcoholism /alcohol abuse; cellular immunity; cytokine; endotoxins; enzyme activity; free radical oxygen; glucose metabolism; human immunodeficiency virus 1; immunopathology; immunoregulation; interleukin 1; laboratory rat; leukocyte oxidative burst; monoclonal antibody; neutrophil; protein kinase C; radioimmunoassay; statistics /biometry; vascular endothelium; virus infection mechanism

APPLICANT'S ABSTRACT: Increased susceptibility to human immunodeficiency virus-I (HIV-1) infection, and complications associated with AIDS among alcoholics is widely recognized. The mechanism for increased propensity to infection is thought to be due to ethanol-mediated dysregulation of lymphocyte and monocyte functions. However, studies that deal alcohol-associated changes in vivo in various functions of hepatic macrophages (Kupffer cells) and other phagocytes during HIV-1 infection are few or lacking. Kupffer cells are primarily involved in clearance of particulate and soluble materials (HIV-1 glycoproteins, endotoxin). Thus, any alteration in phagocyte function during viral entry into the host is a major limiting factor in the survival of HIV. Based on these considerations, the overall objective of this proposal is to examine the mechanisms by which alcohol modulates HIV-1 gp120-induced non-specific immune defense mechanisms, i.e., respiratory burst and cytokine release, by Kupffer cells, endothelial cells and neutrophils in the presence or absence of endotoxemia. This proposal is based on the hypothesis that alcohol is a predisposing factor in HIV-1 infection, endotoxemia and liver disease that could hasten its progression to immunodeficiency/AIDS. Specifically, ethanol-induced spontaneous formation of reactive oxygen intermediates (ROI) leads to enhanced TNF and IL-1 production in hepatic macrophages, that could contribute to the immunopathogenesis of HIV-1 infection and AIDS. Proteins derived from HIV-1, e.g., HIV 1 gp12O, may exacerbate cytokine production in the alcoholic liver. Alcohol induces immunodeficiency through attenuation of antigen (HIV 1 gp12O, zymosan)-induced free radical formation in hepatic phagocytes. Thus, specific aim 1 will examine the effect of chronic and acute alcohol intoxication in the rat model (male Sprague-Dawley rats) on HIV-GP-120-induced oxygen-derived free radical formation and cytokine release (IL-1, TNF) by isolated Kupffer cells, endothelial cells, hepatic and blood neutrophils. Since alcohol withdrawal may also have an impact on these cells, studies on superoxide and cytokine release at appropriate interval following withdrawal or recovery from chronic or acute alcohol intoxication will be performed. The relationship between alcohol-mediated alteration of free radical release and cytokine production induced by HIV gpl20 will be studied, by the use of inhibitors of reactive oxygen species, i.e., superoxide dismutase and catalase. Specific aim 2 will elucidate the effect of alcohol with or without endotoxemia on the activities of protein kinase c and NADPH oxidase and glucose use during HIV-GP-120-(plus PMA or zymosan)-mediated respiratory burst, by analyzing the translocation and activities of these enzymes in cytosolic and membrane fractions of phagocytic cells. HIV GP 120 is currently being tested in one of the major international clinical trials as a potential vaccine against HIV (AIDS). Thus, data that will be generated from these studies will provide important information on the efficacy of HIV GP-120 as a vaccine to stimulate or attenuate non-specific immune functions by phagocytes and its possible adverse side effects in the alcoholic liver.

申请人摘要：对人类免疫缺陷的易感性增加 艾滋病毒I型（HIV-1）感染，以及与艾滋病有关的并发症， 酗酒者是公认的。 增加倾向的机制 感染被认为是由于乙醇介导的 淋巴细胞和单核细胞功能。 然而，研究表明， 酒精相关的肝脏各种功能的体内变化 巨噬细胞（枯否细胞）和其他吞噬细胞在HIV-1感染期间， 很少或缺乏。 枯否细胞主要参与清除 颗粒和可溶性物质（HIV-1糖蛋白、内毒素）。 因此，在本发明中， 在病毒进入宿主期间吞噬细胞功能的任何改变都是 艾滋病病毒存活的主要限制因素。 基于这些 考虑到这些因素，本提案的总体目标是审查 酒精调节HIV-1 gp120诱导的非特异性 免疫防御机制，即，呼吸爆发和细胞因子释放，通过 枯否细胞、内皮细胞和中性粒细胞存在与否 内毒素血症 这一建议是基于这样的假设，即酒精是一种 HIV-1感染、内毒素血症和肝病的易感因素， 可能加速其向免疫缺陷/艾滋病的发展。 具体地说， 乙醇诱导的活性氧中间体（ROI）的自发形成 导致肝巨噬细胞中TNF和IL-1的产生增加， 有助于HIV-1感染和艾滋病的免疫发病机制。 蛋白 来源于HIV-1，例如，HIV 1 gp12O可能会加剧细胞因子的产生， 酒精肝 酒精通过衰减诱导免疫缺陷 抗原（HIV 1 gp12O，酵母聚糖）诱导的肝细胞自由基形成 吞噬细胞 因此，具体目标1将审查慢性和慢性疾病的影响， 急性酒精中毒大鼠模型（雄性Sprague-Dawley大鼠） HIV-GP-120诱导的氧自由基形成和细胞因子 通过分离的枯否细胞、内皮细胞、肝细胞释放（IL-1、TNF 和血液中性粒细胞。 由于酒精戒断也可能对 这些细胞，研究超氧化物和细胞因子释放在适当的 慢性或急性酒精戒断或恢复后的间隔 中毒将被执行。 酒精介导的 HIV诱导的自由基释放和细胞因子产生的改变 将通过使用活性氧物质的抑制剂， 也就是说，超氧化物歧化酶和过氧化氢酶。 具体目标2将阐明 酒精对蛋白质活性的影响 在HIV-GP-120-（加PMA或 酵母聚糖）介导的呼吸爆发，通过分析易位和 这些酶在细胞质和膜组分中的活性 吞噬细胞 HIV GP 120目前正在一个主要的 作为一种潜在的艾滋病毒（艾滋病）疫苗进行国际临床试验。 因此，从这些研究中产生的数据将提供重要的 关于HIV GP-120作为疫苗刺激或 通过吞噬细胞减弱非特异性免疫功能， 酒精肝的副作用