ALCOHOL MODULATES HIV-1 REPLICATION IN LATENT CD4+ CELLS

描述(由申请人提供)：流行病学研究发现 酒精是HIV-1感染的重要危险因素。酒精暴露 增加艾滋病毒-1的复制，加速临床向艾滋病的进展。我们的 长期目标是彻底根除携带整合HIV-1的T细胞 在疾病的临床潜伏期。这样做的目的是 应用是为了更好地理解酒精在人体内的作用机制。 潜伏T淋巴细胞中病毒复制的重新激活。基于 初步结果，我们的假设是酒精/α-CD3共同刺激 在感染病毒的潜伏T淋巴细胞中启动生产性病毒复制 HIV-1。本申请的具体目的如下：(1)确定 酒精诱导潜伏的CD4T细胞感染后再激活的机制 与HIV-1；(2)阐明潜伏的第二信使信号转导 酒精诱导病毒复制；(3)研究白酒口服液对病毒复制的影响 酒精/α-CD3对转录因子核因子-kappaB介导的HIV-1Long的影响 末端重复序列(LTR)转录；以及(4)检测 酒精/α-CD3对细胞因子依赖和核因子-kappaB非依赖性诱导的影响 潜伏的HIV-1复制。我们提出了一种生化方法来探索 酒精对T细胞受体(TCR)/CD3介导的T淋巴细胞的调节能力 外周血中纯化的CD4T细胞的激活作用 淋巴细胞(PBL)。这是基于我们的初步工作，它证明了 酒精和α-CD3共同刺激增强了病毒在体内的复制 潜伏感染的PBL。在这个项目结束时，我们预计 证明酒精可增加TCR/CD3介导的潜伏病毒诱导 在CD4T细胞中。这项研究的意义在于它的重要性 临床意义。过度饮酒可能会加速 潜伏的、无症状的感染进展为艾滋病。此外， 拟议的研究有望揭示抗逆转录病毒的新靶点 治疗。

DESCRIPTION (provided by applicant): Epidemiological studies have identified alcohol as an important risk factor for HIV-1 infection. Alcohol exposure increases HIV-1 replication and accelerates clinical progression to AIDS. Our long-range goal is total eradication of T cells that harbor integrated HIV-1 during the clinically latent phase of the disease. The objective of this application is to better understand the mechanism of alcohol in the reactivation of viral replication in latent T lymphocytes. Based on the Preliminary Results, our hypothesis is that alcohol/alpha-CD3 co-stimulation initiates productive viral replication in latent T lymphocytes infected with HIV-1. The Specific Aims of this application are as follows: (1) to determine the mechanism of alcohol-induced reactivation of latent CD4+ T cells infected with HIV-1; (2) to elucidate the second messenger signaling involved in latent viral replication induced by alcohol; (3) to study the effect of alcohol/alpha-CD3 on transcription factor NF-kappaB-mediated HIV-1 long terminal repeat (LTR) transcription; and (4) to examine the role of alcohol/alpha-CD3 on cytokine-dependent and NF-kappaB-independent induction of latent HIV-1 replication. We propose a biochemical approach to explore the ability of alcohol to modulate T cell receptor (TCR)/CD3-mediated T-lymphocyte activation utilizing purified CD4+ T cells derived from peripheral blood lymphocytes (PBLs). This is based on our preliminary work, which demonstrated that alcohol and alpha-CD3 co-stimulation enhances viral replication in latently infected PBLs. At the conclusion of this project, we expect to demonstrate that alcohol increases TCR/CD3 mediated induction of latent virus in CD4+ T cells. The significance of this study lies in its important clinical implications. Excessive alcohol consumption may hasten the progression of latent, asymptomatic infection to AIDS. In addition, the proposed study is expected to reveal novel target sites for antiretroviral treatment.