Targeting the Cholinergic Pathway in HIV-associated Inflammation and Cognitive Dysfunction

针对 HIV 相关炎症和认知功能障碍的胆碱能通路

基本信息

批准号：
10201539
负责人：
Rebecca Ashare
金额：
$ 73.35万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10201539
关键词：
AIDS/HIV problem Acetylcholine Acetylcholinesterase Address Adverse effects Agonist Alzheimer&apos s Disease Animal Model Anti-Inflammatory Agents Antiinflammatory Effect Attenuated Biological Markers CCL2 gene CD8-Positive T-Lymphocytes Carbon Monoxide Cholinesterase Inhibitors Chronic Cigarette Clinical Cognitive Cognitive deficits Consequences of HIV Cotinine Cross-Over Studies Disease Dose Double-Blind Method Effectiveness Enzymes FCGR3B gene FDA approved Fatigue Galantamine Gene Expression Profile Glycoproteins Guidelines HIV HIV Envelope Protein gp120 HIV Infections HIV antiretroviral HIV-1 HIV-associated neurocognitive disorder HLA-DR Antigens Health Impaired cognition Incidence Individual Infection Inflammation Inflammatory Life Expectancy Measures Mediating Memory Methods Neurobehavioral Manifestations Neurocognition Neurocognitive Neurocognitive Deficit Neurologic Deficit Nicotine Nicotinic Receptors Outcome Pathogenesis Pathway interactions Patient Self-Report Pattern Performance Pharmaceutical Preparations Pharmacological Treatment Pharmacology Phase Placebos Plasma Population Property Quality of life Randomized Rattus Reporting Residual state Role Sampling Severities Short-Term Memory Smoker Smoking Study Subject Survival Rate System T-Cell Activation Testing Therapeutic Tobacco Use Cessation Tobacco use Urine Verbal Learning Viral Load result antiretroviral therapy arm base cholinergic cofactor cytokine desensitization executive function functional disability immune activation immunoregulation improved innovation insight macrophage memory process monocyte new therapeutic target nicotine use non-smoker novel positive allosteric modulator prevent primary outcome processing speed receptor receptor function response therapeutic target therapeutically effective tobacco exposure tobacco user transcriptomics

项目摘要

PROJECT SUMMARY Although anti-retroviral therapy (ART) enhances life expectancy and overall quality of life (QoL), HIV-infected individuals are increasingly vulnerable to non-AIDS-related diseases including HIV-associated neurocognitive disorders (HAND) . Inflammation, particularly activated monocytes/macrophages (M/M), is considered to be a primary mechanism in the pathogenesis of HAND. Tobacco use may further exacerbate inflammation and thus increase the incidence and severity of HAND. Conversely, nicotine alone has anti-inflammatory effects, mainly through activation of the α7 nicotinic receptors (nAChRs) suggesting that stimulating the cholinergic pathway may be a novel therapeutic target to suppress inflammation and reverse or prevent neurocognitive deficits in HIV-1 infection. Consistent with RFA-DA-17-020, this proposal seeks to evaluate a pharmacological treatment that targets cholinergic function, improves neurocognition, and attenuates inflammation, to probe the interaction between inflammation, nicotinic receptors and smoking in HIV-infected people, and potentially mitigate HIV-associated adverse health consequences, including HAND. We will utilize galantamine (GAL), an FDA-approved procognitive medication that increases endogenous levels of acetylcholine by inhibiting the acetylcholinesterase enzyme and acting as a positive allosteric modulator of the α7 nAChRs. Based on evidence that inflammation is implicated in the pathogenesis of HAND, and that GAL has anti-inflammatory properties, we hypothesize that: (1) nAChR modulation by GAL will reduce chronic residual inflammation and improve neurocognition in ART-treated HIV infection; and (2) that these effects will be larger among chronic smokers (vs. nonsmokers) due to the synergistic effects of nicotine and GAL. In this double-blind, placebo- controlled crossover study, HIV-infected individuals (N=120; 60 smokers, 60 nonsmokers) will be randomized to 12 weeks of GAL or placebo, followed by a 4-week washout, then 12 weeks of GAL or placebo (arms switched). All subjects will be stable on ART and the GAL dose will follow FDA guidelines. At the beginning and end of each treatment phase, M/M and T cell activation markers, soluble inflammatory biomarkers, and viral load will be assessed. Monocyte transcriptomics will also be assessed on a subset of the sample (n=60; 30/group). Neurocognition and clinical outcomes (e.g., chronic fatigue, QoL) will be measured at baseline and at 4-week intervals during each treatment phase. The primary outcomes are M/M and T cell activation (CD16, CD163, and CCR2 expression; plasma CCL2 [MCP-1] and sCD14; CD38/HLA-DR on CD8 cells) and neurocognitive performance (processing speed, verbal learning/memory, executive function). Exploratory outcomes include monocyte gene expression patterns and broad plasma cytokine analysis. This innovative approach will provide mechanistic insight into the interactions among nAChR activation, HIV immune activation and pathogenesis, and tobacco use and has translational and therapeutic implications that could improve health outcomes and QoL among HIV-infected individuals.

项目摘要尽管抗逆转录病毒疗法（ART）可以提高预期寿命和整体生活质量（QOL），但感染了HIV 个体越来越容易受到包括与HIV相关的神经认知在内的非AID相关疾病的影响疾病（手）。炎症，特别是活化的单核细胞/巨噬细胞（m/m），被认为是手发病的主要机制。烟草的使用可能会进一步加剧注入，从而增加手的事件和严重性。相反，仅尼古丁具有抗炎作用，主要是通过激活α7烟碱受体（NACHR），这表明刺激胆碱能途径可能是抑制注射和逆转或预防神经认知缺陷的新型热靶 HIV-1感染。与RFA-DA-17-020一致，该提案旨在评估药物治疗靶向胆碱能功能，改善神经认知并减弱注射，以探测炎症，烟碱受体和吸烟的艾滋病毒感染者之间的相互作用，并可能减轻艾滋病毒相关的不良健康后果，包括手。我们将利用Galantamine（GAL）通过FDA批准的预测药物，通过抑制乙酰胆碱的内源性水平乙酰胆碱酯酶酶，充当α7NACHR的阳性变构调节剂。基于在手的发病机理中暗示炎症，并且GAL具有抗炎属性，我们假设：（1）GAL调制的NACHR调制将减少慢性残留炎症和改善艺术治疗的HIV感染中的神经认知；（2）这些效果在慢性中会更大由于尼古丁和gal的协同作用，吸烟者（与非吸烟者）。在这个双盲，安慰剂中 - 受控的跨界研究，HIV感染的个体（n = 120; 60个吸烟者，60名非吸烟者）将被随机分配到12周的GAL或安慰剂，然后进行4周的冲洗，然后进行12周的GAL或安慰剂（武器）切换）。所有受试者将在艺术方面稳定，而GAL剂量将遵循FDA指南。在开始和每个治疗阶段的结束，M/M和T细胞激活标记，固体炎症生物标志物和病毒负荷将被评估。单核细胞转录组学也将在样品的一部分上进行评估（n = 60； 30/组）。神经认知和临床结果（例如，慢性疲劳，QOL）将在基线和在每个治疗阶段以4周的间隔。主要结果是M/M和T细胞激活（CD16， CD163和CCR2表达；等离子体CCL2 [MCP-1]和SCD14； CD38/HLA-DR上的CD8细胞）和神经认知的表现（处理速度，言语学习/记忆，执行功能）。探索性结果包括单核细胞基因表达模式和广泛的血浆细胞因子分析。这种创新方法将提供有关NACHR激活，HIV免疫激活之间相互作用的机械洞察力和发病机理以及烟草使用，并具有转化和治疗的影响，可以改善艾滋病毒感染者的健康结果和质量。