Epigenetic mechanisms underlying cannabinoid modulation of neuroinflammation in HIV/SIV infection

摘要 HIV相关的神经系统疾病（HAND）是一种主要的合并症，影响约30-50%接受HIV治疗的患者。 抑制性抗逆转录病毒治疗的特点是注意力、集中力、决策困难 和记忆力，抑郁和动作迟缓。虽然脑小胶质细胞的慢性激活被认为是 驱动手，分子机制仍然不明确。新出现的证据表明， DNA甲基化异常的机制可能在多发性骨髓瘤的发病机制中起重要作用。 硬化症、帕金森氏症和阿尔茨海默氏症。然而，DNA甲基化在HIV中的作用 诱导的单核细胞/小胶质细胞活化仍然未知。表观遗传标记是可遗传的， 在有丝分裂过程中传递给几代子细胞可能解释了一种潜在的机制， 单核细胞/小胶质细胞活化，这反过来可能有助于维持cART治疗的持续神经炎症 患者我们的初步研究确定了促炎性干扰素刺激的显著上调， 基底神经节中的趋化因子基因，以及 与炎症反应、凋亡、dsDNA损伤反应和氧化应激相关的基因， 结肠上皮慢性SIV感染的猕猴，分别。更重要的是，慢性大麻素 对未接受ART的SIV感染恒河猴的治疗阻止了脑中促炎基因的表达， 表观遗传学改变表明它们在减轻神经炎症和 减少手部相关症状。在拟议的研究中，我们将首次调查DNA的变化， 与δ-9-四氢大麻酚（THC）、大麻二酚、JWH 133（CB 2 R激动剂）诱导的甲基化相关的 通过SIV感染过程抑制单核细胞/小胶质细胞活化。此外，我们将确定 联合抗逆转录病毒治疗（cART）与慢性大麻素治疗对 表观遗传改变、病毒储库、炎症和血液中的内源性大麻素水平， 脑脊液最后，我们将研究THC的受体介导和分子机制， 阻断内质网应激，这是神经退行性疾病发病的关键事件。拟议 研究是高度创新的，并应用最先进的免疫学和分子方法，以填补一个 我们对与HAND相关的表观遗传机制的理解存在重大差距。大麻素 显示出治疗神经系统疾病的巨大希望，拟议的研究是必要的，因为它将 提供了一个基本的理解，其抗- 炎症效应。最后，这些结果将对免疫调节具有重要的治疗意义， 不仅是艾滋病，还有其他慢性神经炎性疾病。

ABSTRACT HIV associated neurological disorder (HAND), a major comorbidity affecting about 30-50% of patients receiving suppressive anti-retroviral therapy is characterized by difficulties with attention, concentration, decision making and memory, depression and slowed movements. Although chronic activation of brain microglia is proposed to drive HAND, the molecular mechanisms remain ill defined. Emerging evidence has shown that epigenetic mechanisms involving aberrant DNA methylation may significantly contribute to the pathogenesis of multiple sclerosis, Parkinson’s and Alzheimer’s disease. Nevertheless, the role of DNA methylation specifically in HIV induced monocyte/microglia activation remains unknown. The fact that epigenetic marks are heritable and passed on to several generations of daughter cells during mitosis might explain a potential mechanism causing monocyte/microglial activation that may in turn help maintain persistent neuroinflammation in cART treated patients. Our preliminary studies identified significant upregulation of proinflammatory interferon stimulated and chemokine genes in basal ganglia and marked alterations in DNA methylation of CpG islands in promoters of genes associated with inflammatory response, apoptosis, dsDNA damage response and oxidative stress in colonic epithelium of chronically SIV-infected macaques, respectively. More importantly, chronic cannabinoid treatment to ART naïve SIV-infected rhesus macaques prevented proinflammatory gene expression in brain and epigenetic alterations suggesting their immense therapeutic potential for attenuating neuroinflammation and reduced HAND related symptoms. In the proposed studies, we will for the first time investigate changes in DNA methylation associated with delta-9-tetrahydrocannabinol (THC), cannabidiol, JWH133 (CB2R agonist) induced suppression of monocyte/microglial activation through the course of SIV infection. Further, we will determine the effect of combination anti-retroviral treatment (cART) in conjunction with chronic cannabinoid treatments on epigenetic alterations, viral reservoir, inflammation and endogenous cannabinoid levels in the blood and cerebrospinal fluid. Finally, we will investigate the receptor mediated and molecular mechanisms by which THC blocks endoplasmic reticulum stress, a key event in the onset of neurodegenerative diseases. The proposed research is highly innovative and applies state of the art immunological and molecular approaches to fill a significant gap in our understanding of the epigenetic mechanisms associated with HAND. As cannabinoids have shown great promise for the treatment of neurological disorders, the proposed studies are necessary, as it will provide a fundamental understanding of the epigenetic and endocannabinoid mechanisms underlying their anti- inflammatory effects. Finally, the results will have important therapeutic implications for immune modulation in not only HIV but also other chronic neuroinflammatory diseases.