ALCOHOL MODULATES HIV-1 REPLICATION IN LATENT CD4+ CELLS

酒精调节潜伏 CD4 细胞中的 HIV-1 复制

• 批准号: 6611469
• 负责人: Xuan Liu
• 金额: $ 14.25万
• 依托单位: CHARLES R. DREW UNIVERSITY OF MED & SCI
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6611469
• 关键词: AIDS; CD3 molecule; HIV infections; T cell receptor; alcoholic beverage consumption; alcoholism /alcohol abuse; cell growth regulation; cytokine; drug interactions; electroporation; enzyme linked immunosorbent assay; flow cytometry; gel mobility shift assay; helper T lymphocyte; human immunodeficiency virus 1; human tissue; latent virus infection; leukocyte activation /transformation; mitogen activated protein kinase; nuclear factor kappa beta; nucleic acid repetitive sequence; pathologic process; polymerase chain reaction; second messengers; virus replication; western blottings

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.

描述（由申请人提供）：流行病学研究已经确定 酒精是HIV-1感染的重要危险因素。 酒精暴露 增加HIV-1的复制并加速临床向AIDS的进展。 我们的 远程目标是完全根除具有综合HIV-1的T细胞 在疾病的临床潜在阶段。 这个目的 应用是更好地了解酒精的机制 潜在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共刺激 引发潜在的T淋巴细胞中的生产性病毒复制 HIV-1。 本应用程序的具体目的如下：（1）确定 酒精诱导的潜在CD4+ T细胞的重新激活的机制 使用HIV-1； （2）阐明潜在的第二个使者信号 酒精引起的病毒复制； （3）研究 转录因子NF-kappab介导的HIV-1长的酒精/α-CD3长 末端重复（LTR）转录； （4）检查 酒精/α-CD3在细胞因子依赖性和NF-kappab诱导的诱导 潜在的HIV-1复制。 我们提出了一种生化方法来探索 酒精调节T细胞受体（TCR）/CD3介导的T淋巴细胞的能力 利用纯化的CD4+ T细胞衍生自外周血的激活 淋巴细胞（PBL）。 这是基于我们的初步工作 酒精和α-CD3共刺激增强了病毒复制 潜在感染的PBL。 在这个项目的结论下，我们希望 证明酒精会增加TCR/CD3介导的潜在病毒诱导 在CD4+ T细胞中。 这项研究的意义在于其重要 临床意义。 过量的饮酒可能会加速 潜在的无症状感染对艾滋病的进展。 另外， 拟议的研究有望揭示抗逆转录病毒的新型靶位点 治疗。