Acute Neural and Immune Effects of Alcohol in People Living with HIV Infection

项目摘要 HIV感染和大量饮酒单独导致系统和神经免疫炎症 系统通过多个机制。艾滋病毒和酒精都会导致肠道微生物移位， 全身免疫激活，血脑屏障受损，以及神经炎症。因为15%的人 艾滋病毒携带者(PLWH)报告在过去30天内大量饮酒，酒精可能会加剧 艾滋病毒的免疫和神经功能障碍是一个严重的公共卫生问题。观测研究环节 在PLWH中使用酒精会导致大脑异常、认知障碍和死亡率增加。但是，直接 关于酒精和艾滋病毒在人类中相互作用的实验证据很少。科布雷干部研究项目1 (RP1)将调查在HIV感染背景下饮酒是否加剧了炎症信号 外周免疫系统和中枢神经系统。具体地说，这项研究将检查急性影响 适量饮酒对免疫生物标记物、神经代谢产物、脑白质和认知的影响 PLWH和健康对照组。我们将招募48名适度饮酒的人，他们的HIV血清状态不同(24名血清阳性 个人，24名血清阴性对照)参与受控饮料给药和 磁共振成像(MRI)。参与者将被随机分为服用安慰剂(0克酒精/千克体重) 体重)或酒精饮料(.60克/公斤；目标血液酒精=.07克/分升)。血液样本将在基线上采集 并在饮用饮料后3小时进行微生物易位的血浆生物标志物检测， 单核/巨噬细胞活化和细胞因子反应。血浆犬尿氨酸与色氨酸的比例将为 作为与艾滋病毒和饮酒行为相关的免疫激活的衡量标准。认识与主观 在实验期间，将使用Cobre临床的标准化测量方法对中毒进行评估 实验室核心。MRI扫描将收集在酒精下降的肢体上，并将重点放在 神经炎症，包括：1)丘脑和额叶白质中的神经代谢物(胆碱、谷氨酸、谷胱甘肽) 物质，使用磁共振波谱；2)白质扩散率和细胞外自由水，使用扩散加权 成像(DWI)。我们假设酒精将在PLWH中诱导更大的促炎作用，相对于 对照，1)外周免疫系统，反映在血浆生物标记物扰动和色氨酸 降解；2)在大脑中，反映在神经代谢变化、扩散性改变和增加 胞外水分。一个探索性的目标验证了PLWH将表现出更大的主观陶醉的预测 以及酒精状态下的认知障碍。跨学科研究团队和导师已经 在生物行为酒精-艾滋病毒研究方面的经验和专业知识，使这一项目能够成功完成。 RP1与科布雷干部的首要目标一致：确定物质使用的机制 加剧慢性病的不良健康后果。结果将促进对致病因素的理解 酒精使用机制，并为预防和治疗与酒精有关的伤害提供信息，特别是在公共卫生部门。

PROJECT ABSTRACT HIV infection and heavy alcohol use independently cause inflammation in systemic and neural immune systems through multiple mechanisms. Both HIV and alcohol induce microbial translocation from the gut, systemic immune activation, compromise of the blood-brain barrier, and neuroinflammation. Because 15% of people living with HIV (PLWH) report heavy drinking in the past 30 days, the potential for alcohol to exacerbate immunological and neural dysfunction in HIV is a serious public health concern. Observational research links alcohol use in PLWH to brain abnormalities, cognitive impairment, and increased mortality. However, direct experimental evidence on alcohol-HIV interactions in humans is scarce. COBRE CADRE Research Project 1 (RP1) will investigate whether alcohol use in the context of HIV infection exacerbates inflammatory signaling in the peripheral immune system and central nervous system. Specifically, the study will examine acute effects of moderate alcohol consumption on immune biomarkers, neurometabolites, brain white matter, and cognition in PLWH and healthy controls. We will recruit 48 moderate drinkers who differ on HIV serostatus (24 seropositive individuals, 24 seronegative matched controls) to participate in controlled beverage administration and magnetic resonance imaging (MRI). Participants will be randomized to consume placebo (0 g alcohol/kg body weight) or alcoholic beverage (.60 g/kg; target blood alcohol=.07g/dL). Blood samples will be taken at baseline and for 3 hours after beverage consumption and assayed for plasma biomarkers of microbial translocation, monocyte/macrophage activation, and cytokine response. The plasma ratio of kynurenine to tryptophan will be used as a measure of immune activation relevant to HIV and drinking behavior. Cognition and subjective intoxication will be assessed during the experiment using the standardized measures from the COBRE Clinical Laboratory Core. MRI scans will be collected on the descending limb of alcohol and will focus on correlates of neuroinflammation, including: 1) neurometabolites (choline, Glx, glutathione) in thalamus and frontal white matter, using MR spectroscopy; 2) white matter diffusivity and extracellular free water, using diffusion-weighted imaging (DWI). We hypothesize that alcohol will induce greater pro-inflammatory effects in PLWH, relative to controls, 1) in the peripheral immune system, as reflected in plasma biomarker perturbations and tryptophan degradation; 2) in the brain, as reflected in neurometabolic changes, diffusivity alterations, and increased extracellular water. An exploratory aim tests the prediction that PLWH will show greater subjective intoxication and cognitive impairment in the alcohol condition. The interdisciplinary research team and mentors have experience and expertise in biobehavioral alcohol-HIV research to enable successful completion of this project. RP1 aligns with the overarching COBRE CADRE goal: to identify mechanisms through which substance use exacerbates adverse health outcomes in chronic disease. Results will advance understanding of pathogenic mechanisms of alcohol use and inform efforts to prevent and treat alcohol-related harms, particularly in PLWH.