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

项目摘要 虽然抗逆转录病毒疗法（ART）提高了预期寿命和总体生活质量（QoL），但艾滋病毒感染者 个人越来越容易受到非艾滋病相关疾病的影响，包括艾滋病毒相关的神经认知功能障碍。 疾病（HAND） . 炎症，特别是活化的单核细胞/巨噬细胞（M/M），被认为是一种炎症反应。 HAND发病的主要机制。吸烟可能会进一步加剧炎症， 增加手的发病率和严重程度。相反，尼古丁单独具有抗炎作用，主要是 通过激活α 7烟碱受体（nAChRs），表明刺激胆碱能途径 可能是一种新的治疗靶点，以抑制炎症和逆转或预防神经认知缺陷， HIV-1感染。与RFA-DA-17 - 020一致，本提案旨在评价药物治疗 靶向胆碱能功能，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， 减轻艾滋病毒相关的不良健康后果，包括手。我们将利用加兰他敏（GAL）， FDA批准的促认知药物，通过抑制 乙酰胆碱酯酶，并作为α 7 nAChRs的正变构调节剂。基于 证据表明炎症与HAND的发病机制有关，GAL具有抗炎作用， 因此，我们假设：（1）GAL对nAChR的调节将减少慢性残留炎症， 改善ART治疗HIV感染者神经认知能力;（2）这些影响在慢性HIV感染者中更大， 吸烟者（与不吸烟者）由于尼古丁和GAL的协同作用。在这个双盲的安慰剂试验中- 一项对照交叉研究，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GAL或安慰剂，随后为4周洗脱期，然后为12周GAL或安慰剂（组 切换）。所有受试者在ART治疗后将保持稳定，GAL剂量将遵循FDA指南。年初 和每个治疗阶段结束时，M/M和T细胞活化标志物，可溶性炎症生物标志物，和 将评估病毒载量。单核细胞转录组学也将在样品的子集上进行评估（n = 60; 30/组）。神经认知和临床结果（例如，慢性疲劳，QoL）将在基线时测量， 在每个治疗阶段每隔4周给药一次。主要结果是M/M和T细胞活化（CD16， CD163和CCR2表达;血浆CCL2 [MCP-1]和sCD14; CD8细胞上的CD38/HLA-DR）， 神经认知表现（处理速度、语言学习/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。这一创新 该方法将提供机制洞察nAChR激活，HIV免疫激活之间的相互作用 和发病机制，以及烟草使用，并具有转化和治疗意义，可以改善 HIV感染者的健康结果和生活质量。

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.