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

• 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
• 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' 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

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。吸烟可能会进一步加剧炎症，从而 增加手部疾病的发生率和严重程度。相反，单独的尼古丁具有抗炎作用，主要是 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 HIV-1 感染。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，以探究 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，包括手。我们将使用加兰他敏 (GAL)，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 乙酰胆碱酯酶并充当 α7 nAChR 的正变构调节剂。基于 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，我们假设：（1）GAL 调节 nAChR 将减少慢性残留炎症和 改善经 ART 治疗的 HIV 感染的神经认知； (2) 这些影响在慢性病中会更大 由于尼古丁和 GAL 的协同作用，吸烟者（与非吸烟者）相比。在这项双盲安慰剂试验中 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 切换）。所有受试者在 ART 治疗中都将保持稳定，并且 GAL 剂量将遵循 FDA 指南。一开始 以及每个治疗阶段的结束、M/M 和 T 细胞激活标记物、可溶性炎症生物标记物，以及 将评估病毒载量。单核细胞转录组学还将对样本的子集进行评估（n=60； 30人/组）。神经认知和临床结果（例如，慢性疲劳，QoL）将在基线和 每个治疗阶段每隔 4 周一次。主要结果是 M/M 和 T 细胞激活（CD16、 CD163 和 CCR2 表达；血浆 CCL2 [MCP-1] 和 sCD14； CD8 细胞上的 CD38/HLA-DR）和 神经认知表现（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。这种创新的 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。