Modeling the effects of chronic marijuana use on neuroinflammation and HIV-related neuronal injury

大麻是美国使用最广泛的非法药物，在人群中不成比例地流行 艾滋病毒携带者。尽管大麻类化合物有望成为艾滋病毒的治疗剂，但长期使用大麻是 也与潜在的神经生物学损害有关。HIV疾病的神经系统并发症仍然是一种 即使在联合抗逆转录病毒治疗的时代，仍然存在临床问题。我们之前的工作证明 长期吸食大麻会加剧与艾滋病毒相关的认知缺陷，即使是在持续感染艾滋病毒的患者中也是如此 抑制，并与艾滋病毒携带者复杂的大脑异常有关。额外的初步报告 数据显示，与不吸食大麻的人相比，吸食大麻的人体内炎性细胞因子水平降低 具有认知功能。建立在我们的神经艾滋病毒和成瘾研究的坚实基础上 多学科团队，这一假设驱动的提议将使用体内模型来研究潜在的 HIV相关脑功能障碍的病理生理机制。使用这种翻译方法，我们的目标是 目的：(1)调查HIV疾病和长期吸食大麻对健康的独立和相加影响 与脑损伤有关的炎症过程；(2)模拟长期使用大麻的纵向关系 与HIV引起的炎症及其与脑损伤的关系；以及(3)确定 大麻素代谢物对炎症和神经元标记物的影响。140名成年人分层的前瞻性队列 大麻状态将完成尖端的神经成像、免疫和细胞因子分析，以及 在两年内进行了三次神经心理测试。利用超高分辨率磁共振 在杜克大学，我们将使用多模式、多参数序列来研究 神经炎性和神经变性过程。基线将包括80名艾滋病毒感染者的对照组。 消极的成年人。中心假说是大麻的使用通过以下两种途径扰乱中枢神经系统 抗炎和神经毒性途径。我们的提案直接响应RFA-DA-20-022，其中要求 机制研究：“查明长期和/或大量使用大麻对 内源性大麻素系统功能与HIV引起的炎症及其对神经的影响 系统功能。“这项研究使用团队科学的方法来处理与NIH艾滋病毒/艾滋病相一致的主题 研究优先事项，包括侧重于持续性炎症和与艾滋病毒相关的共病[不是-- 20-018]。通过考虑美国市场上可获得的大麻的有利和不利影响， 我们的建议具有很强的翻译潜力，可以指导医疗和娱乐的临床建议 艾滋病毒携带者吸食大麻。这一及时的和生态上有效的研究也有望推动我们的 对大麻素调节神经系统疾病的炎症机制的理解 以及艾滋病毒携带者的其他共病。

Marijuana, the mostly widely used illicit drug in the United States, is disproportionately prevalent in persons with HIV. Despite the promise of cannabinoids as a therapeutic agent for HIV disease, chronic marijuana use is also associated with potential neurobiological harms. Neurological complications of HIV disease remain a persistent clinical problem even in the age of combination antiretroviral therapy. Our prior work demonstrates that chronic marijuana use exacerbates HIV-associated cognitive deficits, even in patients with sustained HIV suppression, and is associated with complex brain abnormalities in persons with HIV. Additional preliminary data shows reduced levels of inflammatory cytokines in marijuana users compared to non users that correlate with cognitive function. Building on a strong foundation of neuroHIV and addiction research by our multidisciplinary team, this hypothesis-driven proposal will use an in vivo model to investigate the underlying pathophysiological mechanisms of HIV-associated brain dysfunction. Using this translational approach, we aim to: (1) investigate the independent and additive effects of HIV disease and chronic marijuana use on inflammatory processes linked to brain injury; (2) model the longitudinal relationship of chronic marijuana use to HIV-induced inflammation and its relationship to brain injury; and (3) determine the relationship of cannabinoid metabolites to inflammatory and neuronal markers. A prospective cohort of 140 adults stratified marijuana status will complete cutting-edge neuroimaging, immune and cytokine profiling, and neuropsychological testing three times over 2 years. Capitalizing on ultrahigh-resolution magnetic resonance imaging (MRI) capabilities at Duke, we will use multimodal, multi-parametric sequences to investigate neuroinflammatory and neurodegenerative processes. The baseline will include comparison groups of 80 HIV- negative adults. The central hypothesis is that marijuana use disrupts the central nervous system through both anti-inflammatory and neurotoxic pathways. Our proposal responds directly to RFA-DA-20-022, which calls for mechanistic studies to “discern the impact of chronic and/or heavy use of cannabis on the interaction between endocannabinoid system function and HIV-induced inflammation” and “its consequent effects on nervous system function.” This research uses a team science approach to address topics aligned with NIH HIV/AIDS research priorities, including a focus on persistent inflammation and HIV-relevant comorbid conditions [NOT- 20-018]. By considering both beneficial and adverse effects of marijuana available in the United States market, our proposal has strong translational potential to guide clinical recommendations for medical and recreational marijuana in persons with HIV. This timely and ecologically valid research is also expected to advance our understanding of the inflammatory mechanisms through which cannabinoids modulate neurological disorders and other comorbidities in persons with HIV.