Immune Dys-regulation in HIV-infected women with heavy alcohol consumption

描述(由申请人提供)：酗酒在艾滋病毒感染者中很常见，大量饮酒与艾滋病毒疾病加速发展和不良健康结局有关。这项建议将研究在大量饮酒的HIV感染妇女中CD4T细胞下降和HIV疾病进展的机制。酒精可能导致免疫功能障碍的一个机制是通过诱导微生物移位。我们将研究超过10年观察期的慢性累积暴露(剂量x持续时间)是否与更快的CD4T细胞下降和免疫功能障碍(即免疫激活、炎症和免疫衰老水平的加剧)有关，从而导致艾滋病和非艾滋病共病的早期到来。我们将测试我们的假设，即根据NIAAA的危险饮酒标准定义的重度饮酒(女性，每周7杯或每次3杯)会破坏肠道屏障，导致微生物易位，从而增强系统免疫激活、炎症和衰老；所有这些事件都会导致CD4T细胞下降和艾滋病毒疾病的进展。我们将在纵向队列--女性机构间艾滋病毒研究--的生物标本中进行回溯性研究。作为与该联盟中的另一种UO-1相关的次要目标；关于戒酒药物纳曲酮的随机临床试验，我们将在HIV感染的酗酒者中检查减酒药物纳曲酮是否改善了酒精相关的免疫失调。我们将在从事危险饮酒的HIV感染女性中创建一个免疫标记物(易位、免疫激活、炎症和免疫衰老)的储存库和数据库；该数据库可用于未来与酒精和HIV相互作用的翻译研究：观察性或机械性。该项目拥有跨学科的专业知识，来自艾滋病毒/艾滋病领域的领先临床医生、行为科学家、流行病学家和免疫学家，以成功实施本研究的目的和目标。

DESCRIPTION (provided by applicant): Alcohol consumption is common in HIV infected individuals and heavy alcohol consumption has been associated with accelerated HIV disease progression and poor health outcomes. This proposal will investigate mechanism underlying CD4 T cell decline and HIV disease progression in HIV infected women who engage in heavy alcohol consumption. One mechanism by which alcohol may cause immune dysfunction is by inducing microbial translocation. We will examine whether chronic cumulative exposure (amount x duration) over 10 years of observation period is associated with more rapid CD4 T cell decline and immune dysfunctionality namely exacerbation in levels of immune activation, inflammation and immune senescence leading to early advent of AIDS and Non AIDS co-morbidities. We will test our hypothesis that heavy alcohol consumption, defined using NIAAA criteria for hazardous drinking (for women, >7drinks/week or >3 drinks per occasion), disrupts the gut barrier causing microbial translocation which enhances systemic immune activation, inflammation and senescence; all events that contribute to CD4 T-cell decline and HIV disease progression. We will conduct this study retrospectively in bioreposited specimens from the longitudinal cohort, the Women's Interagency HIV Study. As a secondary aim linked to the other UO-1 in this consortium; a randomized clinical trial on alcohol reduction medication naltrexone, we will examine in subset of HIV infected heavy drinkers, whether alcohol reduction medication, naltrexone improves alcohol related immune dysregulation. We will create a repository and database of immune markers (translocation, immune activation, inflammation, and immune senescence) in HIV infected women who engage in hazardous drinking; which can be used for future translational studies related to alcohol and HIV interaction: observational or mechanistic. This project has a cross discipline expertise, from leading clinicians in the HIV/AIDS field, behavioral scientists, epidemiologist, and immunologist for successful implementation of the aims and objectives of this study.