Mechanism of Cannabidiol Effects on HIV Expression, Neuroinflammation, and HIV Cognitive Disease in Chronically-infected Immunocompetent Mice

大麻二酚对慢性感染免疫功能小鼠的 HIV 表达、神经炎症和 HIV 认知疾病的影响机制

• 批准号: 10686313
• 负责人: Alejandra Borjabad
• 金额: $ 70.55万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686313
• 关键词: Affect; Anti-Inflammatory Agents; Anti-Retroviral Agents; Antigens; Antiinflammatory Effect; Anxiety; Apoptosis; Archives; Astrocytes; Basic Science; Biochemical; Bioinformatics; Biological Assay; Brain; Brain Diseases; CB2 knockout; CNR1 gene; CNR2 gene; Cannabidiol; Cannabinoids; Cannabis; Cell Lineage; Cell Separation; Cells; Chronic; Cognition Disorders; Critical Pathways; DNA; Detection; Disease; Dose; Epigenetic Process; Evaluation; Flow Cytometry; Frequencies; Gene Expression; Gene Expression Profiling; Genes; HIV; HIV Infections; HIV Seropositivity; HIV-associated neurocognitive disorder; Hand; Hypermethylation; IL7 gene; Immune; Immune response; Immune system; Immunity; Immunocompetent; Immunologics; Immunosuppression; Impaired cognition; Impairment; In Vitro; Individual; Infection; Inflammation; Inflammatory; Innate Immune Response; Interferon Receptor; Interferons; Joints; Knockout Mice; Learning; Lymphocyte; Macrophage; Measurement; Mediating; Medicine; MicroRNAs; Microglia; Modeling; Modification; Mononuclear; Mus; National NeuroAids Tissue Consortium; Neurocognitive Deficit; Neuropathy; Pain; Pathology; Pathway interactions; Patients; Peripheral; Peripheral Nervous System Diseases; Persons; Pharmaceutical Preparations; Phosphorylation; Poly I-C; Population; Research; Residual state; Role; Route; Science; Seminal fluid; Signal Pathway; Specificity; Stimulus; System; Systems Biology; Testing; Time; Tissues; Viral; Virus; adaptive immunity; antagonist; antiretroviral therapy; antiviral immunity; behavior test; brain cell; brain dysfunction; brain tissue; chronic infection; drug of abuse; experience; high risk; histone modification; in vivo; inflammatory marker; marijuana use; marijuana user; neuroinflammation; neuropathology; pain relief; posttranscriptional; pre-clinical; pre-clinical research; programs; promoter; receptor; response; single-cell RNA sequencing; transcriptome; transcriptome sequencing; transmission process

This application is submitted in response to RFA-DA-20-022 and proposes basic research non-psychoactive commonly experienced by PLWH. However, its long-term HIV infection and progression of HIV disease remain largely undetermined. Our preliminary results in mice infected by chimeric HIV, EcoHIV, show that CBD has both anti-inflammatory and immunosuppressive functions in the brain; strikingly the canonical innate antiviral effector, interferon (IFN)-, was reduced in brains of infected CBD treated mice. Directly relevant to this RFA, we show that CBD increases HIV expression in mouse brain up to 10-fold. Moreover, despite anti-inflammatory effects of CBD alone, the drug failed to mitigate HIV mediated inflammatory gene expression. These results suggest that CBD use can increase HIV expression in PLWH and thereby exacerbate HIV-related diseases including NCI. We hypothesize that increased HIV brain infection by CBD results from its impairment of antiviral immunity including IFN functions. The Specific Aims are to: 1) Optimize CBD mediated increase in EcoHIV brain infection and assay its consequences in mouse behavioral tests including responses in the presence of antiretroviral drugs and during chronic infection, tests of CB receptor participation using knockout mice, and pilot HIV burden/ expression studies from brains of deceased PLWH using cannabis. 2) Determine beneficial or deleterious effects of CBD on HIV control by immunity in brains of EcoHIV-infected mice including assay of antigen-specific responses ex vivo, innate responses in vivo and ex vivo, and gene expression profiling of brain lymphocyte, macrophage and microglia by single cell RNA- seq and bioinformatics. 3) Using information from Aim 2, test the hypothesis that CBD increases HIV expression in the brain and NCI by disruption of IFN responses including assay of post-transcriptional modification in IFN induction, epigenetic modification in promoters of IFN stimulated genes, and IFN specificity using knockout mice. Our approaches will include combined CBD and antiretroviral treatment of EcoHIV- infected mice, QPCR for measurement of virus burden in tissues, behavioral tests of learning, isolation and functional evaluation of mononuclear cells from the brain, brain cell lineage specific RNA seq, mechanistic studies of CBD effects upon IFN signaling pathways and epigenetic changes determining IFN responsive gene expression, key receptor knockout mice for responses to EcoHIV/CBD, and curated brain tissue from NNTC of HIV-infected persons using cannabis and no other drugs of abuse. This application meets the RFA requirements of “research models of chronic/persistent HIV-induced inflammation under conditions of ART”; for evaluation of “the role of cannabinoids in HIV-associated chronic inflammation”; and to “Delineate ….. beneficial or deleterious effects of cannabinoid use on HIV-induced inflammation”. science and preclinical in EcoHIV-infected mice to model cannabidiol (CBD) effects in people living with HIV (PLWH). CBD, a cannabis component, is freely available and widely used for relieving pain and anxiety effects on

该申请是根据RFA-DA-20-022提交的，并提出了基本 研究 非精神活性 但是，PLWH经历了。 疾病仍然不确定。 该CBD在大脑中具有抗炎和免疫抑制功能 先天的抗抗激素效应子（IFN） - 在被感染的CBD处理的小鼠的大脑中降低。 与此RFA相关，我们表明CBD在小鼠脑中的表达增加了10倍。 尽管仅CBD的抗炎作用，但该药物仍未减轻HIV介导的炎症基因 这些结果表明，CBD的使用可以增加PLWH中的HIV表达 加重HIV相关疾病，包括NCI。 损伤的结果IFN功能是：1） 优化CBD介导的ECOHIV BRASHIN感染的增加和​​测定后果行为 在存在抗逆转录药物和慢性感染期间，在抗逆转录药物存在下包含反应的测试，CB的测试 使用基因敲除小鼠的受体参与，以及死者大脑的试验艾滋病毒负担/表达研究 使用大麻2）确定CBD对HIV控制的有益或有害影响 生态感染的小鼠的大脑，包括对抗原特异性反应的测定，体内先天反应 单个细胞RNA- SEQ和生物信息学3）使用AIM 2的信息，测试CBD增加HIV的假设 通过破坏IFN响应（包括转录后的测定），在大脑和NCI中的表达 IFN指示的修饰，IFN刺激基因启动子的表观遗传修饰和IFN特异性 使用敲除小鼠。 感染的小鼠，qPCR，用于测量组织中病毒burus负担，学习的行为测试，隔离和 来自大脑的单核细胞的功能评估，脑细胞谱系特异性RNA SEQ，机械 CBD对IFN信号通路和表观遗传变化的影响确定IFN反应基因 表达，关键受体基因敲除小鼠，用于对ECOHIV/CBD的反应，并从NNTC中策划了脑组织 艾滋病毒的人使用大麻，没有其他滥用药物。 “慢性/持续性艾滋病毒诱发的炎症的研究模型”； 评估“大麻素在与HIV相关的慢性炎症中的作用”； 或使用大麻素对HIV引起的炎症的有害影响”。 科学和proclinical 在Ecohiv感染的小鼠中，在HIV患者（PLWH）中对大麻二酚（CBD）的影响进行建模 大麻组件免费可用，可用于缓解疼痛和焦虑 影响