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.

艾滋病毒-1仍然是一种不治之症，截至2017年，估计有3000多万人携带艾滋病毒-1 平均每年发生180万新感染病例。高达50%的艾滋病毒携带者(PWH)患有 艾滋病毒相关神经认知障碍(HAND)，尽管有效联合抗逆转录病毒治疗(CART)。 因此，手是导致PWH发病的一个重要原因。Cart无法预防病毒传播 转录和神经认知功能障碍证实了针对潜在基因的辅助治疗的必要性 对手有贡献的机制。在这方面，可促进手机制包括交付 HIV感染的巨噬细胞/小胶质细胞释放的胞外小泡(EVS)中的选择性货物。长期的 这项建议的目的是减轻病毒在中枢神经系统内的致病作用。短期目标包括 阐明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和蛋白质的细胞外小泡，可导致中枢神经系统功能障碍。我们的初步数据 提示大麻二酚和Δ-9-四氢大麻酚可能对 减少HIV-1转录，如反式激活反应(TAR)RNA和全长 基因组RNA的长度，从而导致传染性病毒产量的减少。更多数据表明， 转录的减少导致HIV-1RNA掺入受感染的EV中的减少 细胞，这已被证明有助于受体细胞的功能障碍，包括激活的核因子- Kb途径通过TLR3，增加对感染的易感性。数据表明，这种治疗效果是 进一步放大，因为使用大麻类药物治疗导致电动汽车释放的数量显著减少 从感染HIV-1的细胞中分离出来。我们假设大麻素治疗可能影响宿主细胞通路，包括 自噬和转运所需的内体分选复合体(ESCRT)途径，以改变EV的释放 这可能会在病毒感染中枢神经系统期间缓解EV相关的功能障碍。我们的目标包括：1) 明确大麻素导致HIV-1感染细胞中EV产生和释放减少的机制，以及 2)利用3D神经球研究CBD和THC对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。