cART effects on glial cells

联合抗逆转录病毒疗法（cART）被认为可以显著抑制 艾滋病大流行，越来越多地被用作预防艾滋病毒的预防性治疗 在“高危”人群中传播。尽管有这些治疗进展，艾滋病毒感染 与许多共病状况有关，其中最值得注意的是一系列的 神经认知障碍称为HIV相关的神经退行性疾病（HAND）。的 HIV与cART对HAND的影响尚不清楚。cART不依赖于HIV， 影响中枢神经系统（CNS）的细胞。虽然一些研究表明， 由于cART的神经毒性作用，关于它们对大和小神经胶质细胞的影响知之甚少（例如， 星形胶质细胞和小胶质细胞/巨噬细胞）。神经胶质细胞协调免疫 与神经元和内皮细胞的反应和通信。神经胶质细胞的失调是 与许多神经退行性疾病相关，包括HAND。在本申请中， 目的1：我们将确定cART（Atripla和Triumeq）对表型的影响， 星形胶质细胞、小胶质细胞和单核细胞衍生的巨噬细胞（MDM）的功能。 在目标2中，我们将确定cART对体内神经胶质和神经炎症的影响。 人源化小鼠。总的来说，这些研究将揭示cART对神经胶质细胞及其功能的影响。 对神经元健康和血脑屏障完整性的后续影响以及信息 抗逆转录病毒药物的组合，将保留治疗效果，并具有最小的CNS 失调

Combination antiretroviral therapy (cART) is appropriately credited with dramatically curbing the AIDS pandemic and is increasingly being used as a prophylactic treatment to prevent HIV transmission among “at high-risk” populations. Despite these therapeutic advances, HIV infection is associated with a number of co-morbid conditions, the most notable of which is a spectrum of neurocognitive disorders termed HIV Associated Neurodegenerative Disorders (HAND). The contribution of HIV vs. cART on HAND is not clear. cART, independent of HIV, may negatively impact cells of the Central Nervous System (CNS). While some studies demonstrated direct neurotoxic effects of cART, little is known about their impact on macro and micro glial cells (e.g. astrocytes and microglia/macrophages, respectively). Glial cells coordinate immunologic responses and communication with neurons and endothelial cells. Dysregulation of glial cells is associated with a number of neurodegenerative diseases, including HAND. In this application, in Aim 1 we will determine the impact of cART (Atripla and Triumeq) on the phenotype and function of astrocytes, microglia, and monocyte- derived macrophages (MDMs). In Aim 2, we will determine the impact of cART on glia and neuroinflammation in vivo humanized mice. Collectively, these studies will reveal the impact of cART on glial cells and its subsequent effects on neuronal health and blood brain barrier integrity as well as inform combination of antiretrovirals that will retain therapeutic efficacy with minimal CNS dysregulation.