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.

项目概要尽管抗逆转录病毒治疗 (ART) 可以提高预期寿命和整体生活质量 (QoL)，但 HIV 感染者个人越来越容易感染非艾滋病相关疾病，包括艾滋病毒相关神经认知疾病疾病（手部）。炎症，特别是活化的单核细胞/巨噬细胞 (M/M)，被认为是一种 HAND 发病机制的主要机制烟草使用可能进一步加剧炎症，从而加剧炎症。增加HAND的发生率和严重程度，单独使用尼古丁主要有抗炎作用。通过激活 α7 烟碱受体 (nAChR)，表明刺激胆碱能通路可能是抑制炎症、逆转或预防神经认知缺陷的新治疗靶点与 RFA-DA-17-020 一致，该提案旨在评估药物治疗。以胆碱能功能为目标，改善神经认知，减轻炎症，以探索 HIV 感染者的炎症、烟碱受体和吸烟之间的相互作用，以及潜在的减轻与艾滋病毒相关的不良健康后果，包括 HAND。我们将使用加兰他敏 (GAL)，这是一种 FDA 批准的促认知药物，通过抑制乙酰胆碱来增加内源性乙酰胆碱水平乙酰胆碱酯酶并作为 α7 nAChR 的正变构调节剂。有证据表明炎症与 HAND 的发病机制有关，并且 GAL 具有抗炎作用性质，我们见证了：（1）GAL 调节 nAChR 将减少慢性残留炎症和改善接受 ART 治疗的 HIV 感染者的神经认知；(2) 这些效果在慢性患者中会更大；吸烟者（与非吸烟者）相比，由于尼古丁和 GAL 的协同作用。对照交叉研究，HIV 感染者（N = 120；60 名吸烟者，60 名非吸烟者）将被随机分组至 12 周的 GAL 或安慰剂，然后是 4 周的冲洗，然后是 12 周的 GAL 或安慰剂（手臂所有受试者在 ART 治疗中都将保持稳定，GAL 剂量将遵循 FDA 的指导方针。以及每个治疗阶段的结束、M/M 和 T 细胞激活标记、可溶性炎症生物标记，以及还将评估样本子集（n=60； 30/组）将在基线和临床结果（例如慢性疲劳，QoL）进行测量。每个治疗阶段第 4 周的主要结果是 M/M 和 T 细胞激活（CD16、 CD163 和 CCR2 表达；CD8 细胞上的 CD38/HLA-DR 和血浆 CCL2 [MCP-1] 和 sCD14；神经认知表现（处理速度、语言学习/记忆、探索功能）。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。该方法将为 nAChR 激活、HIV 免疫激活之间的相互作用提供机制见解和发病机制以及烟草使用，并具有可以改善的转化和治疗意义 HIV 感染者的健康结果和生活质量。