ALCOHOL MODULATION OF RECEPTOR SITES FOR HIV AND PRODUCTION OF CHEMOKINES

HIV 受体位点的酒精调节和趋化因子的产生

• 批准号: 6218631
• 负责人: ABRAHAM P. BAUTISTA
• 金额: $ 19.78万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-15 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6218631
• 关键词: CD4 molecule; HIV envelope protein gp120; Kupffer's cell; Macaca mulatta; Streptococcus pneumoniae; alcoholic beverage consumption; bacterial pneumonia; bactericidal immunity; blood chemistry; carbohydrate receptor; cell membrane; chemokine; cytokine receptors; disease /disorder model; ethanol; flow cytometry; immunosuppression; laboratory mouse; laboratory rat; lipopolysaccharides; phagocytosis; pharmacokinetics; receptor binding; receptor expression; simian immunodeficiency virus; virus receptors; virus replication

This proposal is based on the overall hypothesis that alcohol modulates the hepatic immune system at the plasma membrane and molecular levels by altering cell surface receptor expression (binding sites for HIV-1) and production of soluble mediators (chemokines) in hepatic non-parenchymal cells [NPC], i.e., Kupffer cells and sinusoidal endothelial cells. Specifically, acute or chronic alcohol regulates the expression of CD4, chemokine receptors and mannose-specific receptors on hepatic NPC as a result of ethanol-induced alteration in plasma membranes on hepatic NPC. This event could also lead to enhanced intracellular production of H2O2 which in turn activates NF-kappaB. The nuclear translocation and activation of NF-kappaB, a transcription factor, enhances the expression of m-RNA and synthesis of alpha and beta-chemokines. These chemokines could potentially block the binding of HIV-1 or exacerbate its replication in CD4 lymphocytes. The HIV-1 gp120-induced production of beta-chemokines by hepatic NPC may also be modulated by alcohol. The liver is the major organ for microbial clearance and ethanol metabolism. Thus, hepatic cells become susceptible to these agents that could have an impact on the liver itself as well as on the overall homeostasis of the host. For example increased production of pro-inflammatory mediators by hepatic NPC which are the largest contributors of these agents, may also regulate functions of immunocompetent cells in other organs. Thus, based on these considerations, the following specific aims are proposed. Specific aim 1: To determine the effect of acute or chronic alcohol intoxication of hiv-1 GP120 binding, expression of mannose-specific receptors and CD4 on hepatic NPC. The internalization and degradation of HIV-1 gp120 by hepatic NPC will be examined. Specific aim 2: To determine the effect of acute or chronic alcohol intoxication on the intracellular production of H2O2, activation of NF-kappaB, m-RNA expression and secretion of alpha (CINC or IL-8) and beta (Rantes, MIP-1 alpha, MIP-1beta, MCP-1) chemokines in hepatic NPC. The biological activity of HIV-1 gp120 on beta-chemokine production will be assessed, as well as the role of endogenous and exogenous endotoxin on the above parameters (specific aims 1&2). The latter objective will test the hypothesis that chronic alcohol-mediated influx of LPS from the gut to the circulation is responsible, at least in part, for the regulation of hepatic NPC functions at the plasma membrane and molecular levels. Specific aim 3: To determine the effect of chronic alcohol intoxication on hepatic NPC functions, i.e., superoxide anion production, phagocytosis, chemokine and cytokine production, chemokine receptor (CXCR4 & CCR5) expression and SIV gp120 binding. This study will also examine chemokine-mediated SIV-1 replication in a simian model of SIV-1/AIDS. The overall regulation of the above processes by alcohol may further comprise susceptible individuals to HIV-1 infections and opportunistic pathogens associated with this viral infection.

这一建议是基于一个总体假设，即酒精调节 在细胞膜和分子水平上的肝脏免疫系统， 改变细胞表面受体表达（HIV-1的结合位点）， 肝非实质组织中可溶性介质（趋化因子）的产生 细胞[NPC]，即，枯否细胞和肝窦内皮细胞。 具体来说，急性或慢性酒精调节CD 4的表达， 趋化因子受体和甘露糖特异性受体在肝NPC上作为一种 结果乙醇诱导的质膜改变对肝鼻咽癌。 这一事件也可能导致细胞内H2 O2的产生增加 进而激活NF-κ B。核转位和 转录因子NF-κ B的激活增强了 以及α和β趋化因子的合成。这些趋化因子 有可能阻止HIV-1的结合或加剧其复制 在CD 4淋巴细胞中。HIV-1 gp 120诱导β-趋化因子的产生 肝NPC也可以通过酒精调节。肝脏是主要的 用于微生物清除和乙醇代谢的器官。因此，肝细胞 变得对这些可能对肝脏产生影响的药物敏感 自身以及宿主的整体内稳态。例如 增加肝NPC的促炎介质的产生， 是这些代理人的最大贡献者，也可能调节功能 其他器官中的免疫活性细胞。因此，根据这些 考虑到这些因素，提出了以下具体目标。具体目标1： 确定急性或慢性酒精中毒对hiv-1的影响 肝细胞表面GP 120结合、甘露糖特异性受体和CD 4的表达 届全国人大HIV-1 gp 120在肝细胞鼻咽癌中的内化和降解 将被审查。具体目标2：确定急性或慢性感染的影响 慢性酒精中毒对细胞内H2 O2产生的影响， NF-κ B、mRNA表达和α（CINC或 IL-8）和β（Rantes，MIP-1 α，MIP-1 β，MCP-1）趋化因子 肝NPC。HIV-1 gp 120对β-趋化因子的生物学活性 将评估生产，以及内源性和 外源性内毒素对上述参数的影响（具体目标1和2）。的 后一个目标将检验慢性酒精介导的 LPS从肠道流入循环是负责的，至少在 部分，用于调节肝细胞膜上的NPC功能 和分子水平。具体目标3：确定慢性 酒精中毒对肝脏NPC功能的影响，即，超氧阴离子 产生，吞噬作用，趋化因子和细胞因子产生，趋化因子 受体（CXCR 4和CCR 5）表达和SIV gp 120结合。本研究将 还研究了趋化因子介导的SIV-1复制在猿猴模型， SIV-1/艾滋病。酒精对上述过程的总体调节可能 还包括HIV-1感染易感个体， 与这种病毒感染有关的机会致病菌。