2/2 Alcohol associated Comorbidities and Microbiome Evaluation in HIV (ACME HIV)

大量饮酒和HIV-1感染与糖尿病的发生独立相关 大脑功能和认知的异常，以及越来越多的证据表明， 艾滋病毒感染和酒精的影响可能会加剧这些异常。值得注意的是，HIV-1感染 长期酗酒会导致肠道微生物群改变(生物失调)，并增加肠道通透性 和微生物易位(MT)，这是导致局部和全身炎症的主要致病因素。 这种失调的特征是肠道细菌生物多样性的丧失，有益细菌的减少，和/或 有害细菌或促炎细菌的扩张。然而，人们对(I)互动的理解是有限的 酗酒和HIV-1感染对肠道菌群失调的影响及(II)纵向定性 (微生物成员)和数量(相关丰度)决定生物失调。目前的提案 解决这些差距的总体目标是促进针对肠道的合理疗法的发展 生物失调。因此，我们追求一个统一的假设，即在艾滋病毒感染者中，大量饮酒 化合物肠道生物失调和随之而来的外周免疫性炎症导致神经细胞- 炎症和认知功能障碍。为了检验这些假设，我们将从以下地点招募100名HIV+参与者 《30至90天挑战》佛罗里达州SHARC研究(AA020797)这是一项受资助的前瞻性队列研究 登记的酗酒者被要求在30至90天内戒酒，并得到应急措施的帮助 管理(CM)支付和激励性面试。此应用程序，与酒精相关 艾滋病毒的共病和微生物群评估(ACME HIV 2/2)利用现有的资源 “30至90天挑战”佛罗里达SHARC研究：参与者招募，酒精消费测量， 生物标记物和生物标记物收集；在酒精、艾滋病毒和神经成像方面的专业知识。新数据包括： 肠道生物失调的纵向变化，外周炎症的相关变化，以及 认知和神经炎症。作为对RFA-AA-17-014的回应，我们将与圣彼得艾滋病毒基金会合作 研究(ACME HIV 1/2)以证实我们在AIMS 1和2中的发现，并进行联合交叉队列 分析。我们将在HIV+酗酒者中完成以下具体目标：目标1：评估 肠道微生物组的纵向质量和数量变化(生物失调)与非常重的 饮酒。目的2：确定HIV感染和酗酒对肠道生物失调的影响 肠道通透性、微生物易位(MT)和由此引起的外周内毒素血症、免疫 激活和发炎。目的3：探讨微生态失调和外周炎症对脑出血的影响。 神经炎症和认知功能的发展。这些目标的实现将为 针对酒精相关的生物失调的干预，这可以深刻地减少炎症和改善 HIV+酗酒者的认知功能。

Heavy alcohol drinking and HIV-1 infection are independently associated with the development of abnormalities in the brain function and cognition, and increasing evidence indicates that the combinatorial effects of HIV infection and alcohol are likely to worsen these abnormalities. Significantly, both HIV- 1 infection and chronic alcohol abuse cause alterations in gut microbiome (dysbiosis) and increase intestinal permeability and microbial translocation (MT) which are major pathogenic factors driving local and systemic inflammation. The dysbiosis is characterized by loss of gut bacterial biodiversity, a reduction in beneficial bacteria, and/or an expansion of harmful or pro-inflammatory bacteria. However, there is limited understanding of (i) the interactive effects of heavy alcohol drinking and HIV-1 infection on gut dysbiosis and (ii) the longitudinal qualitative (microbial membership) and quantitative (relevant abundance) determinants of dysbiosis. The current proposal addresses these gaps with an overall goal to promote the development of rational therapies targeting gut dysbiosis. Accordingly, we pursue a unifying hypothesis that in HIV-infected individuals, heavy alcohol use compounds gut dysbiosis and consequent peripheral immune inflammation leading to exacerbation of neuro- inflammation and cognitive dysfunction. To test these hypotheses, we will enroll 100 HIV+ participants from “30-to-90-day challenge” Florida SHARC study (AA020797). This is a funded prospective cohort study in which enrolled heavy drinkers are challenged to stop drinking for 30 to 90 days, assisted by contingency management (CM) payments and motivational interviewing. This application, Alcohol associated Comorbidities and Microbiome Evaluation in HIV (ACME HIV 2/2) leverages the existing resources of “30-to-90-day challenge” Florida SHARC study: participant recruitment, measures of alcohol consumption, biospecimen and biomarker collection; expertise in alcohol, HIV and neuroimaging. New data include: longitudinal changes in gut dysbiosis, correlative changes in peripheral inflammation, and measures of cognition and neuroinflammation. In response to RFA-AA-17-014, we will partner with the St. PETER HIV study (ACME HIV 1/2) to corroborate our findings in Aims 1 and 2 and to conduct combined cross-cohort analyses. We will complete the following Specific Aims among HIV+ heavy drinkers: AIM 1: To assess longitudinal qualitative and quantitative changes in the gut microbiome (dysbiosis) associated with very heavy alcohol consumption. AIM 2: To determine the impact of HIV infection and alcohol abuse induced gut dysbiosis on intestinal permeability, microbial translocation (MT), and resultant peripheral endotoxemia, immune activation and inflammation. AIM 3: To investigate the impact of dysbiosis and peripheral inflammation on development of neuro-inflammation and cognitive function. Completion of these aims will lay groundwork for an intervention targeting alcohol-associated dysbiosis, which could profoundly reduce inflammation and improve cognitive functions in HIV+ heavy drinkers.