The Effect Alcohol on SIV Pathogenesis

酒精对 SIV 发病机制的影响

• 批准号: 6454476
• 负责人: Ronald S. Veazey
• 金额: $ 28.34万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6454476
• 关键词: HIV infections; Macaca mulatta; T lymphocyte; alcoholic beverage consumption; cell mediated lymphocytolysis test; communicable disease transmission; cytokine receptors; cytotoxic T lymphocyte; disease /disorder proneness /risk; enzyme linked immunosorbent assay; flow cytometry; helper T lymphocyte; histology; immunocytochemistry; immunopharmacology; in situ hybridization; leukocyte activation /transformation; mucosal immunity; pathologic process; phenotype; receptor expression; simian immunodeficiency virus; virus cytopathogenic effect; virus replication

Increasing evidence indicates that alcohol consumption adversely affects immune function, and may increase the likelihood of HIV transmission and progression to disease. There is a clear association between alcohol use and the risk of contracting HIV infection, yet it remains to be determined whether this is due to immunologic or behavioral mechanisms. Although studies in humans are limited, alcohol has been shown to markedly affect cell-mediated and humoral immune responses. Moreover, consumption of even small amounts of alcohol by humans has been shown to increase HIV replication and affect the production of certain cytokines in cells obtained after alcohol consumption. Alcohol use also causes marked changes in gastrointestinal structure and function, and may adversely affect mucosal immune responses. Since the gastrointestinal tract has recently been shown to be important in the transmission and pathogenesis of AIDS, examining mucosal immune responses during alcohol consumption is crucial for determining the effects of alcohol as a cofactor in transmission and disease progression. We hypothesize that chronic alcohol use; 1) results in an increase in viral target cells specifically in the intestinal tract, resulting in increased susceptibility to infection, and increased viral loads in primary SIV infection, and; 2) results in increased turnover of viral target cells in the intestinal tract, resulting in sustained local viral replication, and an increased rate of disease progression. The Specific Aims of this proposal are: 1) To determine whether chronic alcohol consumption results in an increased rate of mucosal SIV transmission. This will be accomplished by chronically administering alcohol to macaques, and comparing their susceptibility to an atraumatic, intrarectal, low-dose inoculation of SIVmac251, with that of non-alcohol consuming controls. 2) To compare the cellular and molecular changes in the peripheral and mucosal lymphoid tissues of macaques receiving alcohol to those that are not, both before and after SIV infection. Alcohol will be administered to groups of macaques and cells from multiple peripheral and mucosal lymphoid tissues will be serially examined before and during SIV infection. Changes in viral target cells, naive and memory T cell immunophenotyping, chemokine receptor expression, cytokine and SIV-specific cytotoxic T cell (CTL) production, and levels of cellular activation and proliferation will be analyzed in these tissues by various state-of the-art techniques, and compared with viral loads in plasma and tissues by quantitative methods.

越来越多的证据表明，饮酒会对免疫功能产生不利影响，并可能增加艾滋病毒传播和疾病进展的可能性。 饮酒与感染艾滋病毒的风险之间存在明显的关联，但这是否是由于免疫机制或行为机制仍有待确定。尽管对人类的研究有限，但酒精已被证明可以显着影响细胞介导和体液免疫反应。此外，即使人类饮用少量酒精，也会增加艾滋病病毒的复制，并影响饮酒后获得的细胞中某些细胞因子的产生。 饮酒还会引起胃肠道结构和功能的显着变化，并可能对粘膜免疫反应产生不利影响。 由于最近已证明胃肠道在艾滋病的传播和发病机制中很重要，因此检查饮酒期间的粘膜免疫反应对于确定酒精作为传播和疾病进展的辅助因子的影响至关重要。我们假设长期饮酒； 1) 导致肠道中的病毒靶细胞增加，从而增加感染的易感性，并增加原发性 SIV 感染中的病毒载量； 2）导致肠道内病毒靶细胞的周转增加，导致局部病毒持续复制，并加快疾病进展速度。 该提案的具体目标是： 1) 确定长期饮酒是否会导致粘膜 SIV 传播率增加。 这将通过对猕猴长期饮酒，并将其对无创伤、直肠内、低剂量接种 SIVmac251 的敏感性与不饮酒的对照进行比较来实现。 2）比较接受酒精的猕猴与未接受酒精的猕猴在感染SIV之前和之后的外周和粘膜淋巴组织的细胞和分子变化。 在 SIV 感染之前和期间，将对猕猴群进行酒精注射，并对来自多个外周和粘膜淋巴组织的细胞进行连续检查。将通过各种状态来分析这些组织中病毒靶细胞、初始和记忆 T 细胞免疫表型、趋化因子受体表达、细胞因子和 SIV 特异性细胞毒性 T 细胞 (CTL) 产生以及细胞激活和增殖水平的变化。技术，并通过定量方法与血浆和组织中的病毒载量进行比较。