The impact of Cannabis on inflammation and HIV-1 reservoirs in Zambia (Supplement 2)

大麻对赞比亚炎症和 HIV-1 病毒库的影响（补充 2）

• 批准号: 10533925
• 负责人: Charles Wood
• 金额: $ 67.23万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10533925
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adolescent; Affect; Africa; African; Anti-Inflammatory Agents; Antiinflammatory Effect; Autopsy; Brain; Cannabinoids; Cannabis; Cell Line; Cells; Cellular Infiltration; Chronic; Clinical; Collaborations; Country; Coupled; DNA; Disease; Epidemic; Goals; HIV; HIV-1; Heart; High Prevalence; Immune response; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Infrastructure; Investigation; Lead; Life Expectancy; Life Style; Location; Maintenance; Neuraxis; Neuropathogenesis; Pathologic; Pathology; Patient Self-Report; Patients; Pattern; Plasma; Poverty; Prevalence; Property; Recreational Drugs; Reporting; Research Infrastructure; Resources; Sampling; Source; Substance abuse problem; Teaching Hospitals; Testing; Tissue Model; Tissues; Universities; Viral; Viral Load result; Viral reservoir; Virus Latency; Virus Replication; Zambia; antiretroviral therapy; cell type; chronic infection; comorbidity; immune activation; infection rate; inflammatory marker; latent HIV reservoir; marijuana use; marijuana user; mortality; prevent; scale up; viral RNA

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.

摘要 已知影响HIV-1的因素包括共病、慢性炎症和免疫激活 水库和持续感染。大麻等娱乐性药物对HIV-1患者的影响 特别是在HIV-1流行的非洲环境中，研究仍然不足。大多数人 艾滋病毒1型感染者目前生活在非洲，那里贫穷、艾滋病毒1型感染率高， 药物滥用现象并存。在赞比亚，一个处于艾滋病毒-1流行中心的撒哈拉以南国家， 报告了大麻吸毒流行率。再加上该区域艾滋病毒-1流行率高， 药物滥用表明，有必要确定生活方式选择，如使用大麻， 可能影响炎症、HIV-1持续复制或抗逆转录病毒治疗（ART）中的病毒库 对待个人。已经表明，在抗逆转录病毒疗法治疗的个体中， 持续存在并有助于病毒的持续存在。大麻素已被证明可以调节免疫激活 和炎症反应，并已证明在一些慢性炎症的临床影响， 紊乱大麻素的抗炎特性可以减少细胞活化， 持续的低水平HIV-1表达，从而减少潜伏HIV库的大小。基于这些理由， 调查大麻对炎症、潜伏的HIV储库或对 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奋进。 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， 在赞比亚进行这项研究。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，以检验大麻的抗炎特性 将导致减少持续的HIV-1复制，反过来，导致减少的大小和分布， 潜伏的病毒库 我们的总体目标是确定大麻的使用是否与减少当地 免疫激活、HIV-1组织储库的大小和分布改变或持续性病毒感染水平降低 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 组织病理学的患病率、大脑中的炎症和免疫激活水平以及其他 潜在的组织HIV-1储存库，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、HIV-1储存库的分布、大小和维持的影响。使用 独特的死后样本，支持直接测试各种概念，建议从体外 使用组织模型和细胞系进行实验。这项研究还可以提供有用的信息， 制定战略，以减少潜在的水库池，并可能消除他们。