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

基本信息

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
项目类别：
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

项目摘要

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 仍然是一种不治之症，截至 2017 年，估计有超过 3000 万人感染 HIV-1 每年平均新增 180 万艾滋病毒感染者 (PWH)。尽管进行了有效的联合抗逆转录病毒治疗（cART），但仍出现与艾滋病毒相关的神经认知障碍（HAND）。因此，HAND 是 PWH 发病的一个重要原因。 cART 无法预防病毒。转录和神经认知功能障碍证实需要针对潜在的辅助疗法有助于 HAND 的机制在这种情况下，可能有助于 HAND 的机制包括交付 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。该提案的目标是减轻中枢神经系统内病毒介导的发病机制，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我们的初步数据显示，细胞外囊泡含有导致中枢神经系统功能障碍的病毒 RNA 和蛋白质。表明大麻素、大麻二酚 (CBD) 和 Δ9-四氢大麻酚 (THC) 可能有效减少 HIV-1 短非编码 RNA 的转录，例如反式激活反应 (TAR) RNA 和全转录长度基因组 RNA，从而导致感染性病毒产量减少。转录的减少导致 HIV-1 RNA 掺入感染者释放的 EV 的减少细胞，之前已被证明会导致受体细胞功能障碍，包括激活 NF- kB 途径通过 TLR3 并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 数量显着减少，这一效应进一步放大我们认为大麻素治疗可能会影响宿主细胞途径，包括自噬和运输 (ESCRT) 途径所需的内体分选复合物，以改变 EV 释放它可以潜在地减轻 CNS 病毒感染期间与 EV 相关的功能障碍，我们的目标包括： 1) 定义大麻素介导的 HIV-1 感染细胞中 EV 产生和释放减少的机制，以及 2) CBD 和 THC 对使用 3D 神经球的 HIV-1 表达的影响这两者的总体积极影响。目的是强调大麻素在 EV 释放和抑制神经炎症中的作用。