Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
Division of Immunology, Tulane National Primate Research Center, Covington, LA 70433, USA.
Viruses. 2023 Mar 21;15(3):794. doi: 10.3390/v15030794.
Despite the suppression of human immunodeficiency virus (HIV) replication by combined antiretroviral therapy (cART), 50-60% of HIV-infected patients suffer from HIV-associated neurocognitive disorders (HAND). Studies are uncovering the role of extracellular vesicles (EVs), especially exosomes, in the central nervous system (CNS) due to HIV infection. We investigated links among circulating plasma exosomal (crExo) proteins and neuropathogenesis in simian/human immunodeficiency virus (SHIV)-infected rhesus macaques (RM) and HIV-infected and cART treated patients (Patient-Exo). Isolated EVs from SHIV-infected (SHIV-Exo) and uninfected (CTL-Exo) RM were predominantly exosomes (particle size < 150 nm). Proteomic analysis quantified 5654 proteins, of which 236 proteins (~4%) were significantly, differentially expressed (DE) between SHIV-/CTL-Exo. Interestingly, different CNS cell specific markers were abundantly expressed in crExo. Proteins involved in latent viral reactivation, neuroinflammation, neuropathology-associated interactive as well as signaling molecules were expressed at significantly higher levels in SHIV-Exo than CTL-Exo. However, proteins involved in mitochondrial biogenesis, ATP production, autophagy, endocytosis, exocytosis, and cytoskeleton organization were significantly less expressed in SHIV-Exo than CTL-Exo. Interestingly, proteins involved in oxidative stress, mitochondrial biogenesis, ATP production, and autophagy were significantly downregulated in primary human brain microvascular endothelial cells exposed with HIV+/cART+ Patient-Exo. We showed that Patient-Exo significantly increased blood-brain barrier permeability, possibly due to loss of platelet endothelial cell adhesion molecule-1 protein and actin cytoskeleton structure. Our novel findings suggest that circulating exosomal proteins expressed CNS cell markers-possibly associated with viral reactivation and neuropathogenesis-that may elucidate the etiology of HAND.
尽管联合抗逆转录病毒疗法（cART）可抑制人类免疫缺陷病毒（HIV）复制，但仍有 50-60%的 HIV 感染患者患有 HIV 相关神经认知障碍（HAND）。研究表明，由于 HIV 感染，细胞外囊泡（EVs），尤其是外泌体，在中枢神经系统（CNS）中发挥作用。我们研究了循环血浆外泌体（crExo）蛋白与感染猴免疫缺陷病毒（SHIV）的恒河猴（RM）和 HIV 感染及 cART 治疗患者（Patient-Exo）的神经发病机制之间的联系。从感染 SHIV 的（SHIV-Exo）和未感染的 RM（CTL-Exo）中分离的 EV 主要是外泌体（粒径<150nm）。蛋白质组学分析定量了 5654 种蛋白质，其中 236 种蛋白质（~4%）在 SHIV-/CTL-Exo 之间差异表达（DE）。有趣的是，不同的 CNS 细胞特异性标志物在 crExo 中大量表达。与潜伏病毒再激活、神经炎症、神经病理学相关的相互作用以及信号分子相关的蛋白质在 SHIV-Exo 中的表达水平明显高于 CTL-Exo。然而，与线粒体生物发生、ATP 产生、自噬、内吞作用、胞吐作用和细胞骨架组织相关的蛋白质在 SHIV-Exo 中的表达明显低于 CTL-Exo。有趣的是，与氧化应激、线粒体生物发生、ATP 产生和自噬相关的蛋白质在暴露于 HIV+/cART+Patient-Exo 的原代人脑微血管内皮细胞中表达明显下调。我们表明，Patient-Exo 显著增加了血脑屏障通透性，可能是由于血小板内皮细胞黏附分子-1 蛋白和肌动蛋白细胞骨架结构的丢失所致。我们的新发现表明，循环外泌体蛋白表达 CNS 细胞标志物-可能与病毒再激活和神经发病机制相关-这可能阐明 HAND 的病因。
Zotero 插件
