ALCOHOL MEDIATED HIV-1 INFECTIVITY AND REPLICATION

申请人摘要： 众所周知，酒精对免疫系统有抑制作用， 包括T淋巴细胞功能的改变。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 传播并导致艾滋病迅速发展的详细分子 机制尚不清楚。我们的长期目标是开发一种治疗靶点 根除或抑制HIV-1潜伏期的无症状患者， 酗酒。本申请的目的是检查 酒精对静止期和潜伏期病毒感染和复制的影响 T淋巴细胞中心假设，这是基于坚实的初步 结果表明，（1）酒精通过上调CXCR4增强病毒进入 静止T淋巴细胞上的趋化因子共受体和（2）酒精/α-CD 3 共刺激优化潜伏T淋巴细胞中的病毒复制。两 具体的目的是确定（1）CAMP/PKA通路是否参与 酒精诱导CXCR4表达上调;（2）NF κ B通路参与酒精诱导CXCR4表达上调。 酒精/α-CD3共刺激病毒合成。方法将是 利用特异性cAMP/PKA抑制剂检测CXCR4运输、腺苷酸 环化酶活性和LTR转录调节。我们亦会研究 基因检测酒精对细胞周期的影响及NF κ B的参与 转录和上游调控事件。拟议的工作是 创新，因为虽然酒精和艾滋病毒之间的因果关系， 在流行病学研究中已经记录了感染， 酒精对潜伏/静止T淋巴细胞的作用至今尚未得到证实。 我们期望这些研究将确定信号转导 酒精相关HIV的级联反应和基因调控 感染和复制。这些结果将是重要的，因为它们 为设计药物产品提供了新的靶点， HIV感染者潜伏性T淋巴细胞再活化的研究 酗酒此外，通过确认酒精在艾滋病毒中的潜在风险， 感染和/或从慢性感染发展为全面的艾滋病，我们可以 实施一项社会计划，教育公众了解酒精的风险， 无保护的性行为，特别是在少数民族中。而且这些 研究结果将从根本上推动酒精和艾滋病发病机制领域的研究。

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.