The Effect Alcohol on SIV Pathogenesis

酒精对 SIV 发病机制的影响

• 批准号: 6916393
• 负责人: Ronald S. Veazey
• 金额: $ 55.48万
• 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/6916393
• 关键词: HIV infections; Macaca mulatta; T lymphocyte; alcoholic beverage consumption; cell mediated lymphocytolysis test; chemokine receptor; communicable disease transmission; 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HIV传播和发展为疾病的可能性。 酒精使用与感染HIV感染的风险之间存在明显的关联，但这是由于免疫或行为机制是否造成的尚待确定。尽管人类的研究受到限制，但已显示酒精会显着影响细胞介导的体液免疫反应。此外，已经证明，即使是少量的酒精消耗也会增加艾滋病毒的复制，并影响酒精消耗后获得的细胞中某些细胞因子的产生。 酒精使用还会导致胃肠道结构和功能的明显变化，并可能对粘膜免疫反应产生不利影响。 由于最近已显示胃肠道在艾滋病的传播和发病机理中很重要，因此检查饮酒期间粘膜免疫反应对于确定酒精作为辅助因子在传播和疾病进展中的影响至关重要。我们假设慢性饮酒； 1）导致病毒靶细胞在肠道中特别增加，从而导致对感染的敏感性增加，并增加原发性SIV感染的病毒载量，并且； 2）导致肠道病毒靶细胞的周转增加，从而导致局部病毒复制，并增加疾病进展的速度。 该提案的具体目的是：1）确定长期饮酒是否导致粘膜SIV传播率提高。 这将通过长期施用酒精与猕猴进行，并将其敏感性与SIVMAC251的萎缩性，内部直肠，低剂量接种与非酒精消耗对照组进行比较。 2）比较猕猴的外周和粘膜淋巴组织的细胞和分子变化，这些猕猴是在SIV感染之前和之后接受酒精的细胞和粘膜淋巴组织。 酒精将在SIV感染之前和期间对来自多个外周和粘膜淋巴组织的猕猴和细胞组进行施用。病毒靶细胞，天真和记忆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）的产生的变化以及细胞激活和增殖水平将通过各种态度的 - 艺术技术，并通过定量方法与血浆和组织中的病毒载荷进行比较。