Astrocyte-derived exosomes contribute to HIV neuropathogenesis.

摘要 艾滋病病毒感染已成为一种慢性疾病，随着艾滋病病毒感染者（PWH）生活质量的提高， 抗逆转录病毒疗法的疗效。由于慢性炎症，病毒进入中枢神经系统， 大脑内稳态的破坏和衰老，50%的PWH有发展HIV相关认知功能障碍的风险。 （HIV-CI）。星形胶质细胞调节和维持神经元活动和脑内稳态， 变得对炎症有反应。尽管星形胶质细胞感染HIV仍然是一个很难解决的问题。 有争议的问题，它已被证明，这些细胞可以感染艾滋病毒，脱落病毒的 外周，并且可能是重要的HIV储库。我们发现星形胶质细胞的外泌体 PWH患者血浆中活性氧含量显著升高， 在那些有认知障碍的物种（ROS）水平。这一发现证实了 脑和外周神经HIV由星形胶质细胞驱动。此外，我们还检测到了胰岛素受体， 来自PWH的血浆外泌体，在认知障碍患者中显著更高，并且与 外泌体HIV达特蛋白和外泌体ROS水平。因此，星形胶质细胞不仅在HIV感染中发挥作用 通过建立病毒储存库和与威尔斯亲王医院的外围交流，但也可能是 调节PWH脑中的葡萄糖、胰岛素信号和代谢过程。我们假设， HIV感染后，星形胶质细胞变得促炎，改变了它们在CNS中的胰岛素信号， 艾滋病毒感染的发展。在这个过程中，星形胶质细胞释放外泌体到血浆中， 标签，如胰岛素受体（除其他外），这将导致我们发现星形胶质细胞特异性胰岛素- 相关机制发生在PWH使用ART。我们建议，1。表征星形胶质细胞衍生的货物 PWH患者血浆和CSF中的外泌体及其与HIV相关认知障碍的关系 （艾滋病毒-CI）。2.确定并比较暴露于无细胞HIV、血浆和CSF的星形胶质细胞的表型 从PWH在体外。3.探索星形胶质细胞来源的外泌体对神经功能的影响。我们将 探索星形胶质细胞表型和对PWH血浆和CSF响应的差异激活途径 使用ART，重点是胰岛素信号传导和星形胶质细胞衍生的外泌体。

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.