Cannabis, inflammation, and the brain in persons with HIV

项目摘要 在抑制性抗逆转录病毒治疗（ART）期间，HIV感染者（PWH）的慢性炎症持续存在 并且似乎是由低水平的HIV复制、单核细胞/巨噬细胞活化和其他 机制等这种持续性炎症与不良的神经精神疾病（例如，抑郁症， 心理压力、情绪功能障碍）、神经认知和医疗结果。大麻，用于 比没有感染艾滋病毒的人更常见，似乎具有抗炎作用，因此可能 具有炎症和终末器官并发症的治疗应用。大麻素发挥其作用， 部分通过内源性大麻素（EC）系统（ECS），其中包括大麻素受体， 免疫和中枢神经系统细胞的表面。大麻素已证明临床 它对疼痛和恶心等疾病有好处，但对艾滋病毒炎症的影响知之甚少。此外，委员会认为， 大麻暴露的范围（例如，剂量和使用频率）可能有效、无效或不安全 不同的神经精神和医疗条件是未知的。根据RFA-DA-20-022，本申请 建议通过审查长期使用大麻的影响以及 ECS在持续性炎症的PWH谁是抑制性ART。我们建议评估120名参与者 (60威尔斯亲王医院对抑制性抗逆转录病毒疗法和60名艾滋病毒感染者）在大麻使用范围内， 从未对日常使用者使用过大麻。我们将全面评估参与者的多模态体内， 对大麻长期使用对持久性有机污染物 PWH炎症及其对神经精神和神经认知并发症的相应影响。在 体内评估将包括标准化的医学、神经精神病学和神经认知评估， 包括收集脑脊液和血液。该样本中的当前大麻使用者（n=80）也将 使用[（18）F]FEPPA转运蛋白（TSPO）的小胶质细胞活化的新型脑成像进行评估 正电子发射断层扫描在采集的标本中，我们将测量可溶性（例如，支持和反对 炎性细胞因子）和细胞（例如，HLA-DR，CD 38）炎症和免疫激活的生物标志物 以及ECS的组件（例如，大麻素、CB 2受体）。血液样本也将作为 用于评估大麻素作用的离体机理实验的原代细胞培养物的来源， HIV和ART对诸如TREM 2和NLRP 3炎性体的生物学途径的作用。数据从所有 评估和实验将被集中整合和分析，以确定交叉信号， 减少多模式评估的噪音。从本研究中获得的知识将有助于OAR 优先级（例如，合并症，终末器官损伤），并为治疗策略提供有价值的见解， PWH的持续炎症及其健康相关后果。

PROJECT SUMMARY During suppressive antiretroviral therapy (ART), chronic inflammation persists among people with HIV (PWH) and appears to be driven by low levels of HIV replication, monocyte/macrophage activation, and other mechanisms. This persistent inflammation has been linked to adverse neuropsychiatric (e.g., depression, psychological stress, emotion dysfunction), neurocognitive, and medical outcomes. Cannabis, which is used more commonly by PWH than people without HIV, appears to have anti-inflammatory effects and therefore may have therapeutic applications for inflammation and end-organ complications. Cannabinoids exert their effects in part via the endocannabinoid (EC) system (ECS), which includes cannabinoid receptors that are expressed on the surface of cells of the immune and central nervous systems. Cannabinoids have demonstrated clinical benefits for conditions like pain and nausea, but less is known about its effects on inflammation in HIV. Moreover, the range of cannabis exposure (e.g., dose and frequency of use) that may be effective, ineffective, or unsafe for different neuropsychiatric and medical conditions is unknown. In response to RFA-DA-20-022, this application proposes to address key scientific gaps by examining the effects of chronic cannabis use and the role of the ECS in persistent inflammation in PWH who are taking suppressive ART. We propose to assess 120 participants (60 PWH on suppressive ART and 60 HIV- persons) across a spectrum of cannabis use from persons who have never used cannabis to daily users. We will comprehensively evaluate participants with multimodal in vivo and ex vivo assessments of the biological pathways underlying the effects of chronic cannabis use on persistent inflammation in PWH and its corresponding impact on neuropsychiatric and neurocognitive complications. In vivo assessments will include standardized medical, neuropsychiatric, and neurocognitive assessments, including collection of cerebrospinal fluid and blood. Current cannabis users within this sample (n=80) will also be assessed with novel brain imaging of microglial activation with [(18)F]FEPPA translocator protein (TSPO) positron emission tomography. In the collected specimens, we will measure soluble (e.g., pro- and anti- inflammatory cytokines) and cellular (e.g., HLA-DR, CD38) biomarkers of inflammation and immune activation as well as components of the ECS (e.g., anandamide, CB2 receptors). Blood specimens will also serve as the source for primary cell cultures for ex vivo mechanistic experiments that will assess the effects of cannabinoids, HIV, and ART on biological pathways such as the TREM2 and the NLRP3 inflammasome. Data from all assessments and experiments will be integrated and analyzed centrally to identify cross-cutting signals and reduce noise from our multimodal assessments. Knowledge gained from this study will contribute to OAR priorities (e.g., comorbidities, end organ injury) and provide valuable insight into strategies for treatment of persistent inflammation in PWH and its health-related consequences.