Astrocyte-derived exosomes contribute to HIV neuropathogenesis.

星形胶质细胞衍生的外泌体有助于 HIV 神经发病。

• 批准号: 10534936
• 负责人: VALERIE WOJNA
• 金额: $ 22.35万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10534936
• 关键词: Aging; Astrocytes; Bioenergetics; Biological Assay; Brain; Brain-Derived Neurotrophic Factor; Cells; Cerebrum; Chronic; Chronic Disease; Communication; Confocal Microscopy; DLG4 gene; Development; Early Diagnosis; Exposure to; Functional disorder; Future; GLAST Protein; Glial Fibrillary Acidic Protein; Glucose; HIV; HIV Infections; HIV tat Protein; HIV-associated cognitive impairment; Homeostasis; Impaired cognition; In Vitro; Infection; Infiltration; Inflammation; Insulin; Insulin Receptor; Insulin Signaling Pathway; Intervention; Lead; Measures; Metabolic; Metabolism; Modeling; Molecular; Morphology; Nerve Degeneration; Neural Cell Adhesion Molecule L1; Neuraxis; Neurons; Neuropathogenesis; Organoids; Oxidative Stress; Pathway interactions; Patients; Peripheral; Persons; Phenotype; Plasma; Play; Process; Proteomics; Public Health; Quality of life; RNA; Reactive Oxygen Species; Receptor Activation; Risk; Role; Rupture; Synapsins; Synaptic Vesicles; Technical Expertise; Techniques; Viral; Viral reservoir; Virus Shedding; antiretroviral therapy; density; exosome; experimental study; exposed human population; glucose uptake; high risk; improved; induced pluripotent stem cell; insulin signaling; neuroAIDS; neuropathology; response; three dimensional cell culture; viral DNA

Abstract HIV infection has become a chronic disease, with the improved quality of life of people with HIV (PWH) thanks to the efficacy of antiretroviral therapy. Due to chronic inflammation, viral entry into the central nervous system, disruption of brain homeostasis and aging, 50% of PWH are at risk of developing HIV-associated cognitive impairment (HIV-CI). Astrocytes regulate and maintain neuronal activity and brain homeostasis, and thus become reactive in response to inflammation. Although productive infection of astrocytes with HIV is still a matter of debate, it has been demonstrated that these cells can be infected with HIV, shed virus to the periphery, and may be important HIV reservoirs. We have found that exosomes from astrocytes are present and significantly higher in plasma of PWH, and are significantly associated with greater reactive oxygen species (ROS) levels in those with cognitive impairment. This finding confirms communication between the brain and the periphery in NeuroHIV driven by astrocytes. In addition, we have detected the insulin receptor in plasma exosomes from PWH, significantly higher in cognitive impaired patients and positively correlating with exosomal HIV Tat protein and exosomal ROS levels. Therefore, astrocytes not only play a role in HIV infection by the establishment of viral reservoirs and communication with the periphery in PWH, but may also be regulating glucose, insulin signaling, and metabolic processes in the brain of PWH. We hypothesize that upon HIV infection, astrocytes become proinflammatory, altering their insulin signaling in the CNS, and contributing to the development of HIV-CI. In the process, astrocytes release exosomes to the plasma that may contain signatures, such as insulin receptor (among others), which would lead us to uncover astrocyte-specific insulin- related mechanisms occurring in PWH using ART. We propose, 1. Characterize the cargo of astrocyte-derived exosomes from the plasma and CSF of PWH and their association to HIV-associated cognitive impairment (HIV-CI). 2. Determine and compare the phenotype of astrocytes exposed to cell-free HIV, plasma and CSF from PWH in vitro. 3. Explore the effect of the astrocyte-derived exosomes on neuronal function. We will explore astrocyte phenotype and differentially activated pathways in response to plasma and CSF from PWH using ART with emphasis on insulin signaling and astrocyte-derived exosomes.

摘要 艾滋病毒感染已成为一种慢性病，艾滋病毒携带者(PWH)的生活质量得到改善 抗逆转录病毒治疗的疗效。由于慢性炎症，病毒进入中枢神经系统， 大脑动态平衡紊乱和衰老，50%的PWH有发展HIV相关认知的风险 损害(艾滋病毒-CI)。星形胶质细胞调节和维持神经元活动和脑内稳态，从而 对炎症的反应变得活跃。尽管星形胶质细胞感染艾滋病毒仍然是一种 争论的问题是，已经证明这些细胞可以感染艾滋病毒，将病毒传播到 外围，并可能是重要的艾滋病毒宿主。我们已经发现星形胶质细胞的外切体存在。 在PWH患者的血浆中显著升高，并与更高的活性氧显著相关 认知障碍者的物种(ROS)水平。这一发现证实了 由星形胶质细胞驱动的神经艾滋病毒中的大脑和外周。此外，我们还检测到胰岛素受体在 PWH患者血浆Exosome在认知障碍患者中显著升高，并与 胞外体HIV Tat蛋白和胞外体ROS水平。因此，星形胶质细胞不仅在HIV感染中发挥作用 通过建立病毒库并与威斯康星医院的外围通讯，但也可能是 调节PWH患者脑内的葡萄糖、胰岛素信号和代谢过程。我们假设在 HIV感染后，星形胶质细胞变得促炎，改变其在中枢神经系统中的胰岛素信号，并在 对HIV-CI的发展有重要意义。在这个过程中，星形胶质细胞向血浆释放外切体，其中可能含有 信号，例如胰岛素受体(以及其他)，这将引导我们发现星形胶质细胞特有的胰岛素- 应用抗逆转录病毒疗法治疗重症急性胰腺炎的相关机制。我们建议，1.表征星形胶质细胞来源的货物 重型肝炎患者血浆和脑脊液中的外切体及其与HIV相关性认知功能障碍的关系 (HIV-CI)。2.检测和比较无细胞HIV、血浆和脑脊液对星形胶质细胞表型的影响 在体外从PWH中提取。3.探讨星形胶质细胞来源的外切体对神经元功能的影响。我们会 探索星形胶质细胞表型和差异激活途径对PWH血浆和脑脊液的反应 使用抗逆转录病毒治疗，重点是胰岛素信号和星形胶质细胞衍生的外切体。