Cannabis, inflammation, and the brain in persons with HIV

项目总结 在抑制性抗逆转录病毒治疗(ART)期间，艾滋病毒携带者(PWH)的慢性炎症持续存在。 而且似乎是由低水平的艾滋病毒复制、单核/巨噬细胞激活和其他因素驱动的 机械装置。这种持续的炎症与不良的神经精神疾病(例如，抑郁症， 心理压力、情绪障碍)、神经认知和医疗结果。大麻，被用来 与未感染艾滋病毒的人相比，更常见的是PWH，似乎具有抗炎作用，因此可能 对炎症和终末器官并发症有治疗作用。大麻素在体内发挥作用 部分通过内源性大麻素(EC)系统(ECS)，其中包括表达在 免疫和中枢神经系统的细胞表面。大麻素类药物已在临床上证明 对疼痛和恶心等疾病有好处，但对其对艾滋病毒炎症的影响知之甚少。此外， 可能有效、无效或不安全的大麻暴露范围(例如，剂量和使用频率) 对于不同的神经精神和医学状况尚不清楚。响应RFA-DA-20-022，本申请 建议通过审查长期使用大麻的影响和大麻的作用来解决关键的科学差距 持续炎症中的ECS在接受抑制性药物治疗的PWH患者中。我们建议对120名参与者进行评估 (60名威尔斯亲王医院的抑制性抗逆转录病毒药物和60名艾滋病毒携带者) 从未使用过大麻的日常吸毒者。我们将对参与者进行体内和多模式的综合评估 长期使用大麻对持续性影响的生物途径的体外评估 PWH中的炎症及其对神经精神和神经认知并发症的相应影响。在……里面 活体评估将包括标准化的医学、神经精神和神经认知评估， 包括采集脑脊液和血液。这一样本中的当前大麻使用者(n=80)也将 用[(18)F]FEPPA转运蛋白(TSPO)激活小胶质细胞的新型脑显像进行评估 正电子发射断层扫描。在收集的标本中，我们将测量可溶性(例如，支持和反对 炎症细胞因子)和细胞(例如，人类白细胞抗原DR、CD38)炎症和免疫激活的生物标志物 以及ECS的组成部分(例如，阿南达胺、CB2受体)。血液样本也将作为 用于体外机械实验的原代细胞培养的来源，该实验将评估大麻素的影响， HIV，以及TREM2和NLRP3炎症小体等生物途径的ART。数据来自所有 将对评估和实验进行综合和集中分析，以确定贯穿各领域的信号 减少我们的多模式评估带来的噪音。从这项研究中获得的知识将有助于划桨 优先事项(例如，合并症、结束器官损伤)，并提供有价值的见解，以治疗 威斯康星医院的持续性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.