The impact of Cannabis on inflammation and HIV-1 reservoirs in Zambia

摘要 已知的影响HIV-1的因素包括合并症、慢性炎症和免疫激活。 水库和持续性感染。大麻等娱乐用药对HIV-1患者的影响 仍然研究不足，特别是在艾滋病毒-1流行的非洲背景下。大多数的个体 感染艾滋病毒-1的人目前生活在非洲，那里贫穷，艾滋病毒-1感染率高， 物质滥用并存。在处于HIV-1疫情中心的撒哈拉以南国家赞比亚， 据报告，大麻的使用率很高。再加上地区艾滋病毒-1的高流行率， 物质滥用表明，有必要确定生活方式的选择，如使用大麻， 可能会影响抗逆转录病毒治疗(ART)中的炎症、持续的HIV-1复制或病毒库 接受治疗的个体。研究表明，在接受抗逆转录病毒药物治疗的个体中，低水平的免疫激活 持续存在并有助于病毒的持续存在。大麻类化合物已被证明可以调节免疫激活。 和炎症反应，并在一些慢性炎症性疾病中表现出临床影响。 精神错乱。大麻素的抗炎特性可能会减少驱动 持续低水平的艾滋病毒-1表达，从而减少潜在艾滋病毒池的规模。出于这些原因， 调查大麻对炎症、潜伏的艾滋病毒宿主或 HIV-1在包括中枢神经系统在内的各种组织中的复制是一项高度相关的努力。 我们建议利用我们现有的艾滋病毒研究基础设施和专业知识， 在赞比亚为这项研究进行的合作。我们将收集和分析赞比亚HIV-1的尸检病例 阳性，大麻使用者和对照组检验大麻抗炎特性的假设 将导致HIV-1持续复制减少，进而导致病毒的大小和分布减少 潜伏的病毒库。*我们的总体目标是确定大麻的使用是否与当地的减少相关 免疫激活、HIV-1组织储存库的大小和分布改变或持续病毒水平降低 在这些水库中复制。我们的目标将通过解决两个具体目标来实现：1)确定 脑组织病理的患病率、炎症水平和免疫激活等 潜在的组织艾滋病毒-1宿主，并确定与大麻使用的相关性；2)确定大麻是否 使用会影响持续病毒复制的水平或潜伏病毒的大小、分布和细胞组成 组织中的HIV-1储存库。这项研究将有助于更好地了解大麻使用的影响 以及它对炎症的影响，对艾滋病毒-1储存库的分布、大小和维护的影响。对.的使用 独特的尸检样本，支持对体外实验中提出的各种概念进行直接测试 使用组织模型和细胞系进行实验。这项研究也可能提供有用的信息，以 制定减少潜在储集层的战略，并可能消除它们。

Abstract Factors, including co-morbidities, chronic inflammation, and immune activation are known to affect HIV-1 reservoirs and persistent infection. The impact of recreational drugs such as cannabis in HIV-1 patients remains understudied particularly in the African setting where HIV-1 is epidemic. A majority of the individuals infected with HIV-1 currently live in Africa where poverty, high HIV-1 infection rates and increasing rates of substance abuse co-exist. In Zambia, a sub-Saharan country in the heart of the HIV-1 epidemic, high prevalence cannabis use has been reported. Coupled with the high regional HIV-1 prevalence, the reports of substance abuse suggest that there is a need to determine how lifestyle choices, such as use of cannabis, might impact inflammation, persistent HIV-1 replication, or viral reservoirs in anti-retroviral therapy (ART) treated individuals. It has been shown that in aviremic ART treated individuals, low-level immune activation persists and contributes to viral persistence. Cannabinoids have been shown to modulate immune activation and inflammatory responses, and have demonstrated clinical impact in a number of chronic inflammatory disorders. The anti-inflammatory properties of cannabinoids could reduce the cellular activation that drives persistent low-level HIV-1 expression and therefore reduce the size of latent HIV pools. For these reasons, investigation of potential positive or negative effects of cannabis on inflammation, latent HIV reservoirs, or on HIV-1 replication in various tissues including the central nervous system is a highly relevant endeavor. We propose to leverage our existing HIV research infrastructure and expertise resulting from ongoing collaborations in Zambia for this study. We will collect and analyze autopsy cases from Zambian HIV-1 positive, cannabis users and controls to test the hypothesis that the anti-inflammatory properties of cannabis will lead to reduced persistent HIV-1 replication, in turn, leading to a reduction in the size and distribution of latent viral reservoirs.   Our overall goals are to determine whether cannabis use correlates with reduce local immune activation, altered size and distribution of HIV-1 tissue reservoirs or reduced levels of persistent viral replication in those reservoirs. Our goal will be accomplished by addressing two specific aims: 1) Determine the prevalence of tissue pathology, the level of inflammation and immune activation in the brain and other potential tissue HIV-1 reservoirs, and define correlations with cannabis usage; 2) Determine whether cannabis use impacts the level of persistent viral replication or the size, distribution, and cellular composition of latent HIV-1 reservoirs in tissues. This study will lead to a greater understanding of the impact of cannabis usage and its effects on inflammation, on the distribution, the size and maintenance of HIV-1 reservoirs. The use of unique postmortem samples, supports the direct testing of a variety of concepts suggested from in vitro experimentation using tissue models and cell lines. This study may also provide useful information towards developing strategies to reduce the pool of latent reservoirs and possibly eliminate them.