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

项目总结 尽管抗逆转录病毒疗法(ART)提高了预期寿命和整体生活质量(QOL)，但艾滋病毒感染者 个人越来越容易患上与艾滋病无关的疾病，包括艾滋病毒相关的神经认知疾病 精神障碍(手部) 。 炎症，特别是活化的单核/巨噬细胞(M/M)，被认为是一种 手部发病的主要机制。使用烟草可能会进一步加剧炎症，从而 增加手部的发病率和严重程度。相反，尼古丁本身就有抗炎作用，主要是 通过激活α7尼古丁受体(NAChRs)提示刺激胆碱能途径 可能是一个新的治疗靶点，以抑制炎症和逆转或预防神经认知功能障碍 HIV-1感染。与RFA-DA-17-020一致，该提案寻求评估一种药物治疗 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、尼古丁受体和吸烟之间的相互作用，以及潜在的 减轻艾滋病毒相关的不良健康后果，包括手。我们将使用加兰他明(GAL)， FDA批准的认知前药物，通过抑制内源性乙酰胆碱水平 乙酰胆碱酯酶，并作为α7nAChRs的正变构调节剂。基于 有证据表明炎症与手部疾病的发病有关，而且半乳糖具有抗炎作用 ，我们假设：(1)GAL对nAChR的调节将减少慢性残余炎症和 改善接受抗逆转录病毒药物治疗的艾滋病毒感染患者的神经认知能力；以及(2)这些影响在慢性艾滋病患者中更明显。 吸烟者(与不吸烟者相比)是由于尼古丁和GAL的协同作用。在这种双盲的安慰剂中- 对照交叉研究，艾滋病毒感染者(N=120；吸烟者60人，非吸烟者60人)将被随机分组 至12周的GAL或安慰剂，然后是4周的洗涤，然后是12周的GAL或安慰剂(ARM 已切换)。所有受试者在抗逆转录病毒治疗中都是稳定的，GAL剂量将遵循FDA的指导方针。一开始 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，以及 将对病毒载量进行评估。单核细胞转录也将在样本的一个子集上进行评估(n=60； 30个/组)。神经认知和临床结果(例如，慢性疲劳，QOL)将在基线和 在每个治疗阶段间隔4周。主要结果是M/M和T细胞激活(CD16， CD163和CCR2的表达；血浆CCL2[MCP-1]和sCD14；CD8细胞上的CD38/HLA-DR)和 神经认知表现(加工速度、言语学习/记忆、执行功能)。探索性的 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。这是一项创新 该方法将从机制上深入了解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，并具有翻译和治疗的影响，可以改善 艾滋病毒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.