ALCOHOL, HIV1 PROTEINS AND IMMUNOSUPPRESSION

申请者摘要：人类免疫抑制 免疫缺陷病毒(HIV)感染和酗酒在 美国人口和经常共存于同一个人中。目前， 几乎没有关于这两种免疫抑制状态的信息 相互作用以改变宿主防御机制。初步 研究表明，小鼠的许多免疫功能受到损害。 对HIV-1Tat蛋白进行转基因。也有证据表明其他人 HIV编码的蛋白质有助于免疫抑制和免疫 功能障碍。我们的假设是酒精可以起到辅助因子的作用 用HIV编码的蛋白质进一步损害宿主免疫功能 增加宿主对疾病进展的易感性。 这项提议将在表达TAT的转基因小鼠身上检验这一假设 (Tat86)蛋白和表达HIV编码蛋白的HIV小鼠 Gag-Poll缺陷的前病毒DNA，有3个特定的目的。具体目标1至 确定酒精和HIV蛋白对T细胞数量和 T细胞丢失的机制。TAT和HIV小鼠将暴露在酒精中(20% W/v)，2-8周。胸腺和胸腺中T细胞数量 这些动物的脾组织将与来自 酒精处理的非转基因窝产仔每2周一次。每件作品中的动物 不饮酒组作为对照组。我们还将专注于 与细胞凋亡相关的细胞因子的表达 机械装置。由于HIV感染与氧化应激和TAT有关 已知本身对此有贡献，在具体目标2中，我们将评估 酒精对抗氧化防御作用的参数测定 与氧化应激有关。在具体目标3中，我们将比较 酒精处理前后脾淋巴细胞的免疫功能 老鼠。计划中的实验将集中在：1)细胞毒性T淋巴细胞 功能；2)自然杀伤细胞功能；3)释放TH1和TH2 细胞特异性细胞因子。 从这个探索性项目中获得的信息可能会增强我们的 酒精在HIV致病机制中作为辅助因子的认识及新进展 研究的途径。

APPLICANT'S ABSTRACT: Immunosuppression resulting from human immunodeficiency virus (HIV) infection and alcohol abuse are common in the U.S. population and frequently coexist in the same individual. Currently, there is little information on how these two immunosuppressive states might interact with each other to alter host defense mechanisms. Preliminary studies have shown that a number of immune functions are compromised in mice transgenic for the HIV-1 Tat protein. There is also evidence that other HIV-encoded proteins contribute to immunosuppression and immune dysfunctions. It is our hypothesis that alcohol can function as a cofactor with HIV-encoded proteins to further compromise host immune functions and increase host susceptibility to disease progression. This proposal will test this hypothesis in transgenic mice that express Tat (Tat86) protein and HIV mice that express HIV-encoded proteins from a gag-pol defective proviral DNA, and has 3 Specific Aims. Specific Aim 1 to determine the effect of alcohol and HIV proteins on T cell numbers and mechanism of T cell loss. Tat and HIV mice will be exposed to alcohol (20% w/v) in drinking water from 2 to 8 weeks. T cell numbers in thymus and spleen tissues of these animals will be compared to those from alcohol-treated nontransgenic littermates every 2 weeks. Animals in each group without alcohol treatment will serve as controls. We will also focus on expression of cellular factors that are associated with apoptotic mechanisms. Since HIV infection is associated with oxidative stress and Tat itself is known to contribute to it, in Specific Aim 2, we will assess the contribution of alcohol on antioxidant defenses by measuring parameters associated with oxidative stress. In Specific Aim 3, we will compare the immune functions of splenic lymphocytes from alcohol-treated and -untreated mice. Planned experiments will focus on: 1) Cytotoxic T lymphocyte function; 2) Natural killer cell function; and 3) Release of TH1 and TH2 cell-specific cytokines. Information gained from this exploratory project may enhance our understanding of alcohol as a cofactor in HIV pathogenesis and open new avenues of research.