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

点击翻译按钮获取中文摘要

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.