Role of exosome extracellular vesicles in opiate abuse and HIV neuropathogenesis

外泌体细胞外囊泡在阿片滥用和 HIV 神经发病机制中的作用

• 批准号: 9381466
• 负责人: Andrea Denise Raymond
• 金额: $ 21.2万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9381466
• 关键词: AIDS Dementia Complex; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Anti-Retroviral Agents; Antigens; Astrocytes; Biological Assay; Biological Process; Biometry; Brain; Cancerous; Cells; Cerebrospinal Fluid; Confocal Microscopy; Coupled; Couples Therapy; Cross-Sectional Studies; Data; Diagnostic; Disease; Disease Progression; Enzyme-Linked Immunosorbent Assay; Florida; Gene Expression; Gene-Modified; Goals; HIV; HIV Antigens; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Heroin; Heroin Abuse; Human Herpesvirus 4; Immune; Immune response; Impairment; Individual; Infection; International; Laboratories; Mass Spectrum Analysis; Measures; Mediating; Mesenchymal; Microglia; Modification; Morphine; Neuraxis; Neurocognitive; Neurocognitive Deficit; Neuroglia; Neurons; Neuropathogenesis; Opiates; Opioid Peptide; Pathogenesis; Pathway interactions; Patients; Penetrance; Peptides; Peripheral; Plasmids; Play; Proteins; Proteomics; Quality of life; Recording of previous events; Regimen; Reporting; Risk; Role; Severities; Simplexvirus; Statistical Data Interpretation; Substance abuse problem; T-Lymphocyte; Universities; Vesicle; Viral; Viral Load result; base; comparative; endogenous opioids; excitotoxicity; exosome; extracellular; extracellular vesicles; high risk; immunoregulation; improved; in vitro Model; intercellular communication; macrophage; mu opioid receptors; nanoparticle; nanosized; nervous system disorder; neuroAIDS; neuropathology; neurotoxic; neurotoxicity; new therapeutic target; non-drug; novel; opioid abuse; pathogen; potential biomarker; release factor; response; theories; truvada

Project Summary Secreted extracellular vesicles (EVs) may play a role in biological processes and disease pathogenesis. Impact of these EVs on Human Immunodeficiency Virus type 1(HIV-1) infection has only recently started to be investigated. In fact, EVs such as exosomes have been shown to influence cells within the central nervous system (CNS) and modulate immune responses to pathogens. The HIV Negative factor (Nef) is released from nef-transfected or HIV-infected immune cells in exosomes, extracellular nano-sized vesicles generally used for para- or intercellular communication – delivery of antigen, modification of gene expression, and modulation of immune responses. Interestingly, microglia infected with HIV or transfected with a nef-gfp expression plasmid release Nef in exosomes. However, the role this extracellular exosomal Nef (exNef) may have in HIV replication within the CNS and neuropathogenesis is unknown. It is known that HIV infects cells within the brain, persists within the CNS despite successful combination anti-retroviral therapy (cART), and causes neurocognitive impairments such as HIV-associated Neurological Disorder (HAND). Although cART significantly lowers peripheral viral load to undetectable levels(aviremia), HAND is still observed in among 40% of virally suppressed HIV+ individuals. Together these findings suggest that in the presence of cART a novel mechanism not associated with the HIV is at play to induce neurocognitive impairment. Substance abuse could also play a key role in HIV disease progression and the onset of neurocognitive impairment. Opiates such as heroin, and its active metabolite morphine have been shown to increase the rate of HIV disease progression to NeuroAIDS and increase both the risk and severity of HAND in people living with HIV/AIDS (PLWHAs). Given that almost one- third of PLWHAs report heroin abuse, it is important to understand how opiates and cART interplay in HIV disease to cause neurocognitive impairment in order to improve the quality of life for these HIV+ individuals. We hypothesize that opiate-induced modifications in Nef+ EV composition and release exacerbates exNef associated neuronal damage and leads to greater neurocognitive impairment in the context of cART. In this proposal we will investigate in the context of cART and opiates, the impact of extracellular vesicles, specifically exNef released from HIV-infected (or nef- transfected) microglia on neurons in order to understand the mechanism(s) that underlie HIV-induced neurocognitive impairment/HAND during aviremia. We will also perform a cross-sectional study comparing cerebral spinal fluid(CSF) exNef in PLWHAs on cART with a history/current opiate use and neurocognitive impairment/HAND. Findings from this proposal will allow us to demonstrate the role of EVs in the neuropathogenesis induced by the interplay of opiates and HIV in the CNS.

项目摘要 分泌的细胞外蔬菜（EV）可能在生物过程和疾病发病机理中发挥作用。影响 这些关于人类免疫缺陷病毒1型（HIV-1）感染的电动汽车直到最近才开始 调查。实际上，已经证明诸如外泌体等电动汽车会影响中枢神经内的细胞 系统（CNS）并调节病原体的免疫回报。 HIV负因子（NEF）从 外泌体中的NEF转染或HIV感染的免疫小球，细胞外纳米大小的蔬菜通常用于 细胞间通信 - 抗原的递送，基因表达的修饰以及调节 免疫反应。有趣的是，感染HIV或用NEF-GFP表达质粒翻译的小胶质细胞 释放外泌体中的nef。但是，这种细胞外外泌体NEF（EXNEF）在HIV复制中的作用 在中枢神经系统中，神经病发生尚不清楚。众所周知，艾滋病毒感染细胞持续 在中枢神经系统目的地成功组合抗逆转录病毒疗法（CART），并引起神经认知 诸如HIV相关神经系统障碍（HAND）等障碍。虽然马车明显降低 在40％的病毒抑制中，仍观察到外围病毒载荷到无法检测到的水平（白天） 艾滋病毒+个人。这些发现一起表明，在货车存在下，一种新型机制而不是 与HIV相关的是诱导神经认知障碍。滥用药物也可能会发挥钥匙 在艾滋病毒疾病进展和神经认知障碍的发作中的作用。阿片类药物，例如海洛因及其 活跃的代谢产物吗啡已显示可提高HIV疾病进展到神经辅助的速度 增加艾滋病毒/艾滋病（PLWHAS）患者的手的风险和严重性。鉴于几乎一个 PLWHAS报告海洛因滥用的三分之一，重要的是要了解艾滋病毒中如何优化和推车相互作用 疾病引起神经认知障碍，以改善这些HIV+个体的生活质量。我们 假设在NEF+ EV组成中优化诱导的修饰并释放Exnef 相关的神经元损害，导致推车背景下的神经认知障碍更大。在 我们将在购物车的背景下进行调查，并优化细胞外蔬菜的影响， 特别是从HIV感染的（或NEF转染）的小胶质细胞上释放的EXNEF，以了解 艾滋病毒引起的神经认知障碍/手动中的机制。我们也会 进行一项横断面研究，以比较用A的PLWHAS中的脑脊髓液（CSF）EXNEF 历史/当前优化使用和神经认知障碍/手。该提案的发现将使我们能够 证明了电动汽车在中枢神经系统中作战和艾滋病毒相互作用引起的神经病发生中的作用。