Cannabis use frequency and its impact on monocyte-mediated inflammation in HIV patients

项目摘要/摘要 据估计，全球有3700万人感染了人类免疫缺陷病毒(HIV)。组合在一起 抗逆转录病毒疗法(ART)已将艾滋病毒转变为一种慢性感染，预期寿命显著延长。 随着艾滋病毒患者寿命的延长，新的健康问题浮出水面。具体地说，50%的艾滋病毒感染者(艾滋病毒+) 个体出现神经认知障碍，称为艾滋病毒相关性神经认知障碍(HAND)。一把钥匙 导致手部的事件是持续性的低水平慢性炎症，导致神经元损伤和细胞 死亡。HIV诱导的神经炎症的一个主要因素是激活的单核细胞，它们显著地 在HIV相关性痴呆(HAD)患者中升高。HIV感染的一个特征是慢性、系统性的 炎症部分是通过肠道微生物衍生产物的移位而激活的 单核细胞并促进血脑屏障(BBB)的迁移。一旦进入，激活的单核细胞 释放神经毒性和促炎因子(例如，IL-1)，这被认为对手部有贡献。 最近，有证据表明炎性小体的激活是一个重要的因素。 神经炎症和手部的作用机制。在本申请中提出的初步结果表明 单核细胞中炎性小体的激活，如IL-1分泌所证明的，促进了星形胶质细胞的炎症。 这些发现支持单核细胞中炎性小体激活作为驱动机制的关键作用。 神经炎。特别是，死后HIV患者脑组织的免疫组织化学 HAD组有明显的促炎性单核细胞浸润。相比之下，大麻素的暴露 在HIV感染患者中显示抗炎特性，这是我们和其他人已经报道的。反- 大麻的炎症特性很大程度上归因于典型的配体∆9-四氢大麻酚 (THC)，它通过大麻素受体(CB)1和非精神药物- 而大麻二酚(CBD)不通过CB1/CB2起作用。同样，CB2选择性激动剂， JWH-015，代表了一种潜在的策略，用于了解CB2在限制HIV相关的 神经炎。事实上，初步结果表明，CB2选择性激动剂会损害单核细胞。 分泌IL-1，这是炎症和炎症体激活的标志。提出了机理研究的建议 为了验证这一假设：使用HIV+的非大麻受试者的CD16+单核细胞表现出更大的 使用HIV+的受试者与吸食大麻的受试者相比， 这与大麻的使用频率有关。

PROJECT SUMMARY/ABSTRACT An estimated 37 million people worldwide are infected with human immunodeficiency virus (HIV). Combined antiretroviral therapy (ART) has turned HIV into a chronic infection with significantly longer life expectancy. New health issues have surfaced as HIV patients live longer. Specifically, 50% of HIV-infected (HIV+) individuals exhibit neurocognitive impairment, termed HIV-associated neurocognitive disorder (HAND). A key event leading to HAND is persistent low-level chronic inflammation resulting in neuronal damage and cell death. A major contributor to HIV-induced neuroinflammation is activated monocytes, which are significantly elevated in patients’ with HIV-associated dementia (HAD). A hallmark of HIV infection is chronic, systemic inflammation in part through translocation of microbial derived products from the gut which, activates monocytes and promote migration across the blood-brain barrier (BBB). Upon entry, activated monocytes release neurotoxic and proinflammatory factors (e.g., IL-1), which are thought to contribute to HAND. Recently, evidence has emerged implicating the importance of inflammasome activation as a contributing mechanism to neuroinflammation and HAND. Preliminary results presented in this application show that inflammasome activation in monocytes, as evidenced by IL-1 secretion, promotes astroglial cell inflammation. These findings support a critical role for inflammasome activation in monocytes as a mechanism driving neuroinflammation. In particular, immunohistocytochemistry of brain tissue from post-mortem HIV patients with HAD showed significant infiltration of proinflammatory CD16+ monocytes. By contrast, cannabinoid exposure displays anti-inflammatory properties in HIV-infected patients, which we and others have reported. The anti- inflammatory properties of cannabis are attributed largely to the canonical ligand, ∆9-tetrahydrocannabinol (THC), which exerts psychotropic activity through cannabinoid receptor (CB) 1 and the non-psychotropic- mediating CB2, while cannabidiol (CBD) does not act through CB1/CB2. Likewise, the CB2 selective agonist, JWH-015, represents a potential strategy for understanding the role of CB2 in limiting HIV-associated neuroinflammation. In fact, preliminary results demonstrate that a CB2 selective agonist impairs monocyte secretion of IL-1, a hallmark of inflammation and inflammasome activation. Mechanistic studies are proposed to test the hypothesis: CD16+ monocytes from non-cannabis using HIV+ subjects exhibit greater inflammasome formation and subsequent astrocyte activation compared to cannabis using HIV+ subjects, which is associated with the frequency of cannabis use.