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。尽管有 流行病学证据表明酒精可能是艾滋病毒的危险因素 传播并导致艾滋病快速进展的详细分子 机制尚不清楚。我们的长期目标是开发一种治疗靶点 根除或抑制无症状患者的HIV-1潜伏期 酗酒。此应用程序的目标是检查 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。建立在坚实的初步基础上的中心假说 结果是：(1)酒精通过上调CXCR4促进病毒侵入 静止期T淋巴细胞表面趋化因子共受体与(2)酒精/α-CD3 共刺激优化了潜伏T淋巴细胞中的病毒复制。两个人 具体目的是确定(1)cAMP/PKA通路是否参与 酒精诱导CXCR4表达上调和(2)NFkB途径参与 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转运、腺苷 环化酶活性与LTR转录调控。我们亦会研究 酒精对细胞周期的影响及NFkB的基因检测 转录和上游调控事件。建议的工作是 创新，因为尽管酒精和艾滋病毒之间的因果关系 流行病学研究已经记录了感染，其直接影响是 酒精对潜伏期/静止期T淋巴细胞的影响直到现在才被证实。 我们期望这些研究将确定信号转导 级联反应与酒精相关HIV相关基因的调控 感染和复制。这些结果将是重要的，因为他们 为设计抗肿瘤药物提供了新的靶点 HIV感染者体内病毒潜伏T淋巴细胞的再激活 酗酒。此外，通过确认酒精对艾滋病毒的潜在风险， 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，教育公众有关酒精和 无保护措施的性行为，尤其是在少数民族人群中。此外，这些 这一结果将从根本上推进酒精和艾滋病毒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.