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

基本信息

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
项目类别：
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

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

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项目摘要

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引起全身和神经免疫的炎症通过多种机制进行系统。艾滋病毒和酒精都会引起肠道的微生物易位，全身免疫激活，血脑屏障的妥协和神经炎症。因为15％患有艾滋病毒（PLWH）的人报告了过去30天的大量饮酒，这可能会使酒精恶化 HIV中的免疫学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 PLWH中的酒精饮酒可对脑异常，认知障碍和死亡率增加。但是，直接关于人类酒精-HIV相互作用的实验证据很少。山核桃干部研究项目1 （RP1）将调查在HIV感染中使用酒精是否加剧了炎症信号传导周围免疫系统和中枢神经系统。具体而言，该研究将检查免疫生物标志物，神经代谢物，脑白质和认知的适度饮酒 PLWH和健康对照。我们将招募48位在HIV血清的中等饮酒者（24种血清阳性个人，24个血清匹配的对照），以参与受控饮料管理和磁共振成像（MRI）。参与者将被随机消耗安慰剂（0克酒精/公斤身体重量）或酒精饮料（.60 g/kg；靶血液酒精= .07g/dl）。基线将采集血液样本饮料消耗后3小时，并分析了微生物易位的血浆生物标志物，单核细胞/巨噬细胞激活和细胞因子反应。 Kynurenine与色氨酸的血浆比率将是用作与艾滋病毒和饮酒行为有关的免疫激活的量度。认知和主观在实验期间，将使用鞋底临床的标准措施评估中毒实验室核心。 MRI扫描将在酒精的下降肢体上收集，并将集中于神经炎症，包括：1）丘脑和额叶白色的神经代谢物（胆碱，GLX，谷胱甘肽）物质，使用MR光谱法； 2）使用扩散加权的白质扩散率和细胞外无水水成像（DWI）。我们假设酒精会在PLWH中引起更大的促炎作用控制，1）在外围免疫系统中，如等离子体生物标志物扰动和色氨酸的反映降解; 2）在大脑中，如神经代谢变化，扩散率改变并增加细胞外水。探索目的测试PLWH将显示出更大的主观中毒的预测和酒精条件下的认知障碍。跨学科研究团队和导师有生物行为酒精-HIV研究的经验和专业知识，可以成功完成该项目。 RP1与总体毛线干部的目标一致：确定使用物质使用的机制加剧了慢性疾病的不良健康结果。结果将提高对病原体的理解酒精使用机制，并为预防和治疗与酒精有关的危害的努力，特别是在PLWH中。