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.

项目概要 分泌的细胞外囊泡 (EV) 可能在生物过程和疾病发病机制中发挥作用。 这些 EV 对 1 型人类免疫缺陷病毒 (HIV-1) 感染的影响最近才开始 事实上，外泌体等 EV 已被证明可以影响中枢神经系统内的细胞。 系统（CNS）并调节对病原体的免疫反应。 外泌体中的 nef 转染或 HIV 感染的免疫细胞，细胞外纳米大小的囊泡通常用于 细胞旁或细胞间通讯——抗原的传递、基因表达的修饰以及基因表达的调节 提示，小胶质细胞感染了 HIV 或转染了 nef-gfp 表达质粒。 在外泌体中释放 Nef 然而，这种细胞外外泌体 Nef (exNef) 可能在 HIV 复制中发挥作用。 中枢神经系统和神经发病机制尚不清楚，已知艾滋病毒会感染大脑内的细胞并持续存在。 尽管成功进行了联合抗逆转录病毒治疗（cART），但它仍然存在于中枢神经系统内，并导致神经认知障碍 尽管 cART 显着降低了 HIV 相关神经系统疾病 (HAND) 等损伤。 外周病毒载量达到不可检测的水平（无病毒血症），但在 40% 的病毒抑制患者中仍观察到 HAND 这些发现共同表明，在存在 cART 的情况下，HIV + 个体并不存在新的机制。 与艾滋病毒相关的药物滥用也可能是导致神经认知障碍的一个关键因素。 在艾滋病毒疾病进展和海洛因等阿片类药物及其神经认知障碍的发生中的作用。 活性代谢物吗啡已被证明会增加艾滋病毒疾病进展为神经艾滋病的速度 增加 HIV 感染者/艾滋病患者 (PLWHA) 的手部感染风险和严重程度 鉴于几乎一- 三分之一的艾滋病毒感染者报告滥用海洛因，了解阿片类药物和 cART 在艾滋病毒中如何相互作用非常重要 疾病导致神经认知障碍，以改善这些艾滋病病毒感染者的生活质量。 阿片类药物引起的 Nef+ EV 成分和释放的改变使 exNef 恶化 相关的神经元损伤，并导致 cART 背景下更大的神经认知障碍。 这项提案我们将在 cART 和阿片类药物的背景下研究细胞外囊泡的影响， 特别是 exNef 从神经元上感染 HIV（或 nef 转染）的小胶质细胞中释放出来，以便理解 我们还将研究无病毒血症期间 HIV 引起的神经认知障碍/HAND 的机制。 进行一项横断面研究，比较接受 cART 治疗的 PLWHA 中的脑脊液 (CSF) exNef 与 历史/当前阿片类药物使用和神经认知障碍/HAND 将使我们能够 证明 EV 在中枢神经系统中阿片类药物和 HIV 相互作用诱导的神经发病机制中的作用。