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

酒精对艾滋病毒感染者的急性神经和免疫影响

• 批准号: 10259692
• 负责人: Mollie A Monnig
• 金额: $ 26.11万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10259692
• 关键词: Acute; Address; Age; Alcohol consumption; Alcoholic Beverages; Alcohols; Anti-Inflammatory Agents; Beverages; Biological Assay; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Circulation; Blood specimen; Body Weight; Brain; CCL2 gene; Centers of Research Excellence; Choline; Chronic Disease; Clinical; Cognition; Cognitive deficits; Consumption; Control Groups; Diffuse; Diffusion Magnetic Resonance Imaging; Environment; Exhibits; Glutathione; Goals; HIV; HIV Infections; HIV Seropositivity; Health; Heavy Drinking; Hour; Human; Immune; Immune System Diseases; Immune system; Immunologic Markers; Immunologics; Impaired cognition; Impairment; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; Interdisciplinary Study; Interleukin-1 beta; Interleukin-6; Intoxication; Kynurenine; Laboratories; Limb structure; Link; MRI Scans; Macrophage Activation; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Mediating; Mentors; Methods; Neuraxis; Neurobiology; Neurocognitive; Neuroglia; Neuronal Dysfunction; Observational Study; Outcome; Participant; Pathogenicity; Pathway interactions; Peripheral; Pilot Projects; Placebos; Plasma; Production; Prospective cohort study; Protocols documentation; Public Health; Randomized; Reporting; Research; Research Project Grants; Signal Transduction; Socioeconomic Status; Structure; TNF gene; Testing; Thalamic structure; Tryptophan; United States; Viral Proteins; Water; addiction; alcohol content; alcohol effect; alcohol response; biobehavior; brain abnormalities; cerebral atrophy; cytokine; design; disorder risk; drinking; drinking behavior; experience; experimental study; extracellular; gastrointestinal; gut-brain axis; immune activation; interest; men; microbial; monocyte; mortality; mortality risk; multidisciplinary; neuroimaging; neuroinflammation; neurotoxic; novel; prevent; recruit; relating to nervous system; response; seropositive; standardize measure; substance use; white matter

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.

项目摘要 HIV感染和大量饮酒独立地引起全身和神经免疫系统的炎症。 通过多种机制。艾滋病毒和酒精都会诱导肠道微生物移位， 全身免疫激活、血脑屏障受损和神经炎症。因为15%的 艾滋病毒感染者（PLWH）报告在过去30天内大量饮酒，酒精可能会加剧 HIV免疫和神经功能障碍是一个严重的公共卫生问题。观察研究链接 酒精的使用对PLWH的大脑异常，认知障碍和死亡率增加。然而，直接 关于酒精与艾滋病毒在人体内相互作用的实验证据很少。COBRE CADRE研究项目1 (RP1)将研究在HIV感染的情况下饮酒是否会加剧炎症信号， 外周免疫系统和中枢神经系统。具体而言，该研究将研究 适度饮酒对免疫生物标志物、神经代谢物、脑白色物质和认知的影响 PLWH和健康对照。我们将招募48名中度饮酒者，他们的HIV血清状态不同（24名血清阳性 个体，24个血清阴性匹配对照）参与受控饮料施用， 磁共振成像（MRI）。受试者将随机摄入安慰剂（0 g酒精/kg体重 体重）或酒精饮料（0.60 g/kg;目标血液酒精= 0.07 g/dL）。将在基线时采集血液样本 并在饮用饮料后3小时内检测微生物易位的血浆生物标志物， 单核细胞/巨噬细胞活化和细胞因子应答。犬尿氨酸与色氨酸的血浆比率将为 用于衡量与艾滋病毒和饮酒行为相关的免疫激活。认知与主观 在实验过程中，将使用COBRE临床试验的标准化测量方法评估中毒情况。 实验室核心MRI扫描将收集酒精的下行分支，并将重点关注以下相关因素： 神经炎症，包括：1）丘脑和额叶白色神经代谢产物（胆碱、Glx、谷胱甘肽） 2）白色物质扩散率和细胞外游离水，使用扩散加权 磁共振弥散成像（DWI）。我们假设，酒精会诱导PLWH更大的促炎作用，相对于 对照，1）外周免疫系统，如血浆生物标志物扰动和色氨酸 降解; 2）在大脑中，反映在神经代谢变化，扩散率改变和增加 胞外水一个探索性的目标测试预测，PLWH将显示更大的主观中毒 和认知障碍。跨学科的研究团队和导师有 在生物行为酒精-艾滋病毒研究方面的经验和专业知识，使该项目能够成功完成。 RP 1与COBRE CADRE总体目标一致：确定物质使用的机制 加剧了慢性病的不良健康后果。结果将促进对致病性 酒精使用的机制，并为预防和治疗酒精相关伤害的努力提供信息，特别是在PLWH中。