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

项目摘要 据估计，全世界有3 700万人感染了人体免疫缺陷病毒（艾滋病毒）。组合 抗逆转录病毒疗法（ART）已将艾滋病毒变成一种慢性感染，预期寿命大大延长。 随着艾滋病毒感染者寿命的延长，新的健康问题也浮出水面。50%的艾滋病毒感染者（HIV+） 个体表现出神经认知损害，称为HIV相关的神经认知障碍（HAND）。一个关键 导致HAND的事件是持续性低水平慢性神经炎症，导致神经元损伤和细胞凋亡。 死亡HIV诱导的神经炎症的一个主要贡献者是活化的单核细胞，其显著地 在艾滋病相关痴呆患者中升高。活化的CD 16+单核细胞在淋巴细胞中被HIV感染。 外周并迁移穿过血脑屏障（BBB）以释放HIV病毒体和神经毒素， 促炎因子在进入CNS之前，静息（CD 16-）单核细胞转变为CD 16+单核细胞。 通过对机制知之甚少，包括干扰素α（IFNα），一种有效的抗病毒细胞因子， 由浆细胞样树突状细胞（pDC）产生，这一观察结果与IFNα基因特征一致， HIV患者的单核细胞。HIV患者的慢性IFNα产生与神经认知功能有关 损伤与此同时，IFNα也激活CD 8 + T细胞，这些细胞从体循环中募集到交叉免疫。 的BBB。一旦进入血管周围空间，活化的单核细胞和CD 8 + T细胞与星形胶质细胞相互作用， 驱动慢性神经炎症反应，导致神经元破坏和认知功能下降。 有趣的是，大麻，其中有成分（例如，Δ9-四氢大麻酚（THC））具有免疫 抑制和抗炎活性，被HIV患者广泛使用（约25-37%）。的 大麻素治疗对HIV患者的有益与有害作用仍然未知和研究不足。 初步结果显示，THC抑制IFNα介导的CD 16-至CD 16+单核细胞的转变， CD 8 + T细胞上的IL-7受体上调。此外，艾滋病毒+大麻使用者（MJ+） CD 16+单核细胞与HIV+MJ-相比。初步数据也提出了使用一种新的全人类共培养 系统证明，当与星形胶质细胞共培养时，单核细胞和CD 8 + T细胞都显著驱动 星形胶质细胞源性炎症介质的分泌，包括IL-6和IP-10， 四氢大麻酚提出了机制研究来验证假设：大麻素抑制干扰素-α介导的 外周单核细胞和CD 8 + T细胞活化及其对星形胶质细胞功能的不利影响， 这是HIV相关慢性神经炎症的关键过程。

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.