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

大量饮酒和HIV-1感染独立地与 大脑功能和认知的异常，越来越多的证据表明， 艾滋病毒感染和酒精的影响可能会使这些异常恶化。值得注意的是，HIV- 1感染 和慢性酒精滥用导致肠道微生物组的改变（生态失调），并增加肠道通透性 和微生物易位（MT），它们是驱动局部和全身炎症的主要致病因素。 微生态失调的特征在于肠道细菌生物多样性的丧失、有益细菌的减少和/或肠道细菌生物多样性的减少。 有害或促炎细菌的扩张。然而，人们对（i）互动的理解有限 大量饮酒和HIV-1感染对肠道生态失调的影响，以及（ii）纵向定性 （微生物成员）和数量（相关丰度）的决定因素。现时的建议 解决这些差距，总体目标是促进针对肠道的合理疗法的发展， 生态失调。因此，我们追求一个统一的假设，即在艾滋病毒感染者中， 化合物肠道生态失调和随之而来的外周免疫炎症，导致神经- 炎症和认知功能障碍。为了验证这些假设，我们将招募100名HIV+参与者， “30-90天攻毒”佛罗里达SHARC研究（AA 020797）。这是一项受资助的前瞻性队列研究， 登记的重度饮酒者被要求戒酒30至90天， 管理层（CM）薪酬和动机面试。此应用程序，酒精相关 艾滋病毒合并症和微生物组评价（ACME HIV 2/2）利用现有资源， “30-90天挑战”佛罗里达SHARC研究：参与者招募，酒精消费量测量， 生物标本和生物标志物收集;酒精、艾滋病毒和神经成像方面的专业知识。新数据包括： 肠道生态失调的纵向变化，外周炎症的相关变化，以及 认知和神经炎症。为了响应RFA-AA-17-014，我们将与圣彼得艾滋病毒 研究（ACME HIV 1/2），以证实我们在目标1和2中的发现，并进行联合跨队列研究， 分析。我们将在HIV+重度饮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定性和定量变化（生态失调）与非常重的 酒精消费。目的2：确定HIV感染和酒精滥用引起的肠道生态失调的影响 对肠道通透性、微生物易位（MT）以及由此产生的外周内毒素血症、免疫 激活和炎症。目的3：研究微生态失调和外周炎症对 神经炎症和认知功能的发展。这些目标的实现将为 针对酒精相关的生态失调的干预，这可以大大减少炎症， HIV+重度饮酒者的认知功能。

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.