ALCOHOL MEDIATED HIV-1 INFECTIVITY AND REPLICATION

酒精介导的 HIV-1 感染和复制

• 批准号: 6654948
• 负责人: Xuan Liu
• 金额: $ 14.3万
• 依托单位: CHARLES R. DREW UNIVERSITY OF MED & SCI
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-07 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6654948
• 关键词: CD28 molecule; CD3 molecule; HIV infections; T lymphocyte; adenylate cyclase; alcoholism /alcohol abuse; cell cycle; clinical research; cyclic AMP; cytokine receptors; enzyme activity; genetic transcription; human immunodeficiency virus 1; human subject; nuclear factor kappa beta; protein kinase A; receptor expression; virus replication

APPLICANT'S ABSTRACT: Alcohol has been known to have a suppressive effect on the immune system, including alteration in the T-lymphocyte function. Although there are epidemiologic evidences to suggest that alcohol may be a risk factor in HIV transmission and cause rapid progression to AIDS, a detailed molecular mechanism is not known. Our long-range goal is to develop a therapeutic target to either eradicate or suppress HIV- 1 latency in asymptomatic patients who abuse alcohol. The objective of this application is to examine the effect of alcohol on viral infection and replication in quiescent and latent T-lymphocytes. The central hypothesis, which is based on solid Preliminary Results, is that (1) alcohol enhances viral entry by up-regulating CXCR4 chemokine co-receptor on quiescent T-lymphocytes and (2) alcohol/alpha-CD3 co-stimulation optimizes viral replication in latent T-lymphocytes. The two specific aims are to determine whether (1) CAMP/PKA pathway is involved in CXCR4 up-regulation induced by alcohol and (2) NFkB pathway is involved in alcohol/alpha-CD3 co-stimulation of viral synthesis. The approach will be to utilize specific cAMP/PKA inhibitors to examine CXCR4 trafficking, adenylate cyclase activity and LTR transcription regulation. We will also study the effect of alcohol on cell cycle and the involvement of NFkB by examining gene transcription and the upstream regulatory events. The proposed work is innovative, because although the causal relationship between alcohol and HIV infection has been documented in epidemiological studies, a direct effect of alcohol on latent/quiescent T-lymphocytes has not been demonstrated until now. It is our expectation that these studies will identify the signal transduction cascade and the regulation of the genes involved in alcohol related HIV infection and replication. These results will be significant because they provide a novel target site for designing pharmaceutical product to suppress reactivation of viral latent T-lymphocyte in HIV patient with history of alcohol abuse. In addition, by confirming the potential risk of alcohol in HIV infection and/or progression from chronic infection to full-blown AIDS, we can implement a social program to educate the public about the risk of alcohol and unprotected sex, especially in the minority population. Furthermore, these results will fundamentally advance the field of alcohol and HIV pathogenesis.

申请人的摘要： 众所周知，酒精对免疫系统有抑制作用， 包括改变T淋巴细胞功能。虽然有 流行病学证据表明酒精可能是艾滋病毒的危险因素 传播并导致艾滋病的快速发展，详细的分子 机制尚不清楚。我们的远程目标是开发一个治疗目标 消除或抑制无症状患者的HIV-1潜伏期 滥用酒精。该应用的目的是检查 静态和潜在的病毒感染和复制的酒精 T淋巴细胞。中央假设，基于固体初步 结果是（1）通过上调CXCR4，酒精可以增强病毒的进入 静态的T-淋巴细胞和（2）酒精/α-CD3的趋化因子共受体。 共刺激优化了潜在T淋巴细胞中的病毒复制。两个 具体目的是确定（1）CAMP/PKA途径是否参与 酒精引起的CXCR4上调和（2）NFKB途径参与 酒精/α-CD3病毒合成的共刺激。方法将是 利用特定的CAMP/PKA抑制剂检查CXCR4运输，腺苷酸盐 环化酶活性和LTR转录调节。我们还将研究 酒精对细胞周期和NFKB的参与的影响通过检查基因 转录和上游监管事件。拟议的工作是 创新，因为尽管酒精与艾滋病毒之间的因果关系 感染已在流行病学研究中记录在 迄今为止，尚未证明潜在/静止的T淋巴细胞上的酒精。 我们期望这些研究将确定信号转导 级联和调节与酒精相关的HIV涉及的基因 感染和复制。这些结果将很重要，因为它们 提供一个新型的目标站点，用于设计药品以抑制 病毒潜在T淋巴细胞在HIV患者患有病史患者病史的重生 酗酒。另外，通过确认艾滋病毒中酒精的潜在风险 感染和/或从慢性感染到成熟艾滋病的进展，我们可以 实施一个社会计划，以教育公众关于酒精风险和 无保护的性别，尤其是在少数族裔人口中。此外，这些 结果从根本上可以推进酒精和HIV发病机理的领域。