Cannabinoids Modulate Immune Cell-provoked Astrocyte Functions to Suppress HIV-Associated Neuroinflammatory Responses

项目总结 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神经炎，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相关痴呆症患者中升高。被激活的CD16+单核细胞被HIV感染 并通过血脑屏障(BBB)释放HIV病毒粒子和神经毒素和 促炎因子。静息状态(CD16-)单核细胞在进入中枢神经系统前向CD16+细胞转化 通过知之甚少的机制，包括一种有效的抗病毒细胞因子--干扰素α升高 由浆细胞样树突状细胞产生，观察到与干扰素α基因特征一致的 来自HIV患者的单核细胞。艾滋病患者慢性干扰素α的产生与神经认知有关 减损。同时，干扰素α也激活CD8+T细胞，这些T细胞从体循环中被招募来跨越 BBB。一旦进入血管周围空间，激活的单核细胞和CD8+T细胞就会与星形胶质细胞相互作用 导致慢性神经炎性反应，导致神经元破坏和认知功能下降。 有趣的是，大麻含有具有免疫力的成分(如Δ9-四氢大麻酚) 抑制和抗炎活性，被艾滋病毒患者广泛使用(约25%-37%)。这个 大麻素治疗对HIV患者的益处与有害作用仍不清楚，也未得到充分研究。 初步结果显示，THC抑制干扰素α介导的CD16+单核细胞向CD16+单核细胞转化 CD8+T细胞IL-7受体上调。此外，艾滋病毒+大麻使用者(MJ+)的血液循环较少 CD16+单核细胞与HIV+MJ-比较。初步数据也用一种新颖的全人类共文化进行了展示。 系统显示单核细胞和CD8+T细胞在与星形胶质细胞共培养时显著驱动 星形胶质细胞衍生的炎症介质的分泌，包括IL-6和IP-10，这一反应被抑制 太好了。机制研究被用来验证这一假设：大麻类物质抑制干扰素-α介导的 外周血单核细胞和CD8+T细胞活化及其对星形胶质细胞功能的不利影响 这是HIV相关慢性神经炎的关键过程。

PROJECT SUMMARY 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 disorders (HAND). A key event leading to HAND is persistent low-level chronic neuroinflammation 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. Activated, CD16+ monocytes are infected by HIV in the periphery and migrate across the blood-brain barrier (BBB) to release HIV virions and neurotoxic and proinflammatory factors. Before entering the CNS, resting (CD16–) monocytes transition into the CD16+ through poorly understood mechanisms including elevated interferon alpha (IFNα), a potent antiviral cytokine produced by plasmacytoid dendritic cells (pDC), an observation consistent with the IFNα gene signature in monocytes from HIV patients. Chronic IFNα production in HIV patients has been linked to neurocognitive impairment. In parallel, IFNα also activates CD8+ T cells, which are recruited from systemic circulation to cross the BBB. Once in the perivascular space, activated monocytes and CD8+ T cells interact with astrocytes to drive a chronic neuroinflammatory response leading to destruction of neurons and declining cognative function. Interestingly, cannabis, which has constituents (e.g., Δ9-tetrahydrocannabinol (THC)) possessing immune suppressive and anti-inflammatory activity, is widely used (approximately 25-37%) by HIV patients. The beneficial vs. deleterious effects of cannabinoid therapy in HIV patients remains unknown and understudied. Preliminary results show that THC suppresses IFNα-mediated CD16– to CD16+ monocyte transition as well as IL-7 receptor upregulation on CD8+ T cells. Moreover, HIV+ marijuana-users (MJ+) have fewer circulating CD16+ monocytes compared to HIV+MJ-. Preliminary data is also presented using a novel all human coculture system demonstrating that both monocytes and CD8+ T cells, when cocultured with astrocytes significant drive the secretion of astrocyte-derived inflammatory mediators, including IL-6 and IP-10, a response suppressed by THC. Mechanistic studies are proposed to test the hypothesis: Cannabinoids suppress interferon-α-mediated monocyte and CD8+ T cell activation in the periphery and their detrimental effects on astrocyte function, all of which are key processes in HIV-associated chronic neuroinflammation.