Effect on CBD on Exosome release from CNS infected cells

CBD 对中枢神经系统感染细胞外泌体释放的影响

• 批准号: 9884894
• 负责人: Fatah Kashanchi
• 金额: $ 21.1万
• 依托单位: GEORGE MASON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884894
• 关键词: 3-Dimensional; Affect; Anti-Retroviral Agents; Autophagocytosis; Binding; Biological Assay; Blood; Brain; Cannabidiol; Cannabinoids; Cell Culture Techniques; Cell model; Cells; Cellular Stress; Central Nervous System Viral Diseases; ChIP-seq; Collaborations; Complex; DNA; Data; Development; Disease; Down-Regulation; Functional disorder; Gene Expression; Genetic Transcription; Goals; HIV; HIV therapy; HIV-1; HIV-associated neurocognitive disorder; Human; In Vitro; Individual; Infection; Length; Light; Mediating; Metabolism; Microglia; Morbidity - disease rate; NF-kappa B; Neurocognitive; Neurons; Pathogenesis; Pathology; Pathway interactions; Predisposition; Production; RNA; Reporting; Role; Serotonin Receptor 5-HT1A; Sorting - Cell Movement; T-Lymphocyte; TLR3 gene; Testing; Tetrahydrocannabinol; Therapeutic; Therapeutic Effect; Time; Untranslated RNA; Validation; Viral; Viral Proteins; Virus; Virus Replication; antiretroviral therapy; base; cannabinoid treatment; cytokine; exosome; extracellular vesicles; follow-up; genomic RNA; induced pluripotent stem cell; innovation; macrophage; nerve stem cell; nervous system disorder; neuroinflammation; prevent; promoter; receptor binding; repaired; response; restoration; targeted treatment; three dimensional cell culture; vesicular release; viral RNA

HIV-1 remains an incurable disease and as of 2017 over 30 million people were estimated to be living with HIV-1 with an average of 1.8 million new infections occurring annually. Up to 50% of people with HIV (PWH) suffer from HIV-associated neurocognitive disorders (HAND) despite effective combination anti-retroviral therapy (cART). HAND therefore represents a significant cause of morbidity in PWH. The inability of cART to prevent viral transcription and neurocognitive dysfunction confirms the need for adjunct therapies that target underlying mechanisms that contribute to HAND. In this context, mechanisms that may contribute to HAND include delivery of selective cargo in extracellular vesicles (EVs) released from HIV-infected macrophages/microglia. The long-term goal of this proposal is to mitigate virally-mediated pathogenesis within the CNS. The short term goals including elucidating the role of the cannabinoids in the inhibition of viral transcription and the reduction in the release of extracellular vesicles containing viral RNAs and proteins which cause CNS dysfunction. Our preliminary data suggests that the cannabinoids, cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), may be effective in reducing HIV-1 transcription of both short, non-coding RNA such as trans-activating response (TAR) RNA and full- length genomic RNA, thereby resulting in a decreased production of infectious virus. Additional data indicates that the reduction in transcription results in a decreased incorporation of HIV-1 RNA into EVs released from infected cells, which has been previously shown to contribute to dysfunction in recipient cells including activation of the NF- kB pathway through TLR3 and increased susceptibility to infection. The data suggests this therapeutic effect is further amplified as treatment with cannabinoids results in a significant reduction in the number of EVs released from HIV-1 infected cells. We hypothesize that cannabinoid treatment may affect host cell pathways, including autophagy and the endosomal sorting complexes required for transport (ESCRT) pathways, to alter EV release which can potentially mitigate EV-related dysfunction during viral infection of the CNS. Our Aim include: 1) To define the mechanisms of cannabinoid-mediated decreased EV production and release in HIV-1 infected cells, and 2) Effect of CBD and THC on HIV-1 expression using 3D neurospheres. The overall positive impact of these two aims are to highlight the role of cannabinoids in EV release and dampening of the neuroinflammation.

HIV-1仍然是一种无法治愈的疾病，截至2017年，估计有超过3000万人感染HIV-1 平均每年有180万新感染病例。高达50%的艾滋病毒感染者（PWH）患有 尽管联合抗逆转录病毒治疗（cART）有效，但仍存在HIV相关神经认知障碍（HAND）。 因此，手是威尔斯亲王医院发病的重要原因。cART无法预防病毒感染， 转录和神经认知功能障碍证实了需要辅助治疗， 有助于手的机制。在这方面，可能有助于加强人力资源和发展的机制包括提供 HIV感染的巨噬细胞/小胶质细胞释放的细胞外囊泡（EV）中的选择性货物。长期 该提议的目的是减轻CNS内病毒介导的发病机制。短期目标包括 阐明了大麻素在抑制病毒转录和减少病毒释放中的作用， 含有病毒RNA和蛋白质的细胞外囊泡，导致CNS功能障碍。我们的初步数据 表明大麻素，大麻二酚（CBD）和Δ9-四氢大麻酚（THC），可能是有效的 减少HIV-1短的非编码RNA如反式激活反应（TAR）RNA和全长的转录， 长度的基因组RNA，从而导致感染性病毒的产生减少。其他数据表明， 转录的减少导致HIV-1 RNA掺入感染者释放的EV中的减少， 细胞，其先前已被证明有助于受体细胞中的功能障碍，包括NF-κ B的活化。 通过TLR 3的kB途径和增加对感染的易感性。数据表明，这种治疗效果是 随着大麻素治疗导致释放的EV数量显著减少， 从HIV-1感染的细胞。我们假设大麻素治疗可能会影响宿主细胞途径，包括 自噬和转运所需的内体分选复合物（ESCRT）途径，以改变EV释放 其可以潜在地减轻CNS病毒感染期间EV相关的功能障碍。我们的目标包括：1） 确定大麻素介导的HIV-1感染细胞中EV产生和释放减少的机制， 2)CBD和THC对使用3D神经球的HIV-1表达的影响。这两个方面的总体积极影响 目的是强调大麻素在EV释放和抑制神经炎症中的作用。