Extracellular HIV-1 viral protein R affects astrocytic glyceraldehyde 3-phosphate dehydrogenase activity and neuronal survival.
Extracellular HIV-1 viral protein R affects astrocytic glyceraldehyde 3-phosphate dehydrogenase activity and neuronal survival.
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DOI：
10.1007/s13365-013-0170-1
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发表时间：
2013-06
影响因子：
3.2
通讯作者：
Wigdahl, Brian
中科院分区：
文献类型：
--
作者：
Ferrucci, Adriano;Nonnemacher, Michael R.;Wigdahl, Brian
关键词：
细胞外人类免疫缺陷病毒1型(HIV-1)病毒蛋白R(VPR)是一种在病毒生命周期内完成多种功能的多效性蛋白。虽然VPR被广泛描述为一种细胞内蛋白，但人们对其作为细胞外蛋白的作用知之甚少。事实上，在HIV-1感染者的血液、血清和脑脊液中都检测到了HIV-1 VPR，在晚期疾病中浓度越来越高。为了确定外源性VPR在HIV相关中枢神经系统功能障碍中的作用，原代培养的人胚胎星形胶质细胞暴露于重组VPR后，细胞内两种基本代谢物(ATP和GSH)的含量呈时间和剂量依赖性下降。此外，暴露于外源性VPR后，caspase活性增加，促炎症细胞因子IL-6和IL-8以及趋化因子、单核细胞趋化蛋白-1和迁移抑制因子的分泌增加。细胞外VPR还通过损害GAPDH活性抑制糖酵解途径，导致ATP水平下降。细胞内ATP的减少增加了活性氧的积累，降低了GSH的浓度，这影响了氧化应激途径中的几个基因。此外，SK-N-SH神经母细胞瘤细胞株暴露于外源性VPR处理的星形胶质细胞的条件培养液中，GSH的合成减少，导致细胞凋亡。这些观察表明，VPR在改变星形细胞新陈代谢和间接影响神经元存活方面发挥了作用。我们提出了一个模型，可以解释在HIV-1疾病过程中观察到的一些神经损伤，从而神经认知障碍。
Extracellular human immunodeficiency virus type type 1 (HIV-1) viral protein R (Vpr) is a pleiotropic protein accomplishing several functions within the viral life cycle. While Vpr has been described extensively as an intracellular protein, very little is known about its role as an extracellular protein. In fact, HIV-1 Vpr has been detected in the blood, serum, and cerebrospinal fluid of HIV-1-infected patients, with concentrations increasingly higher in late-stage disease. To determine the role exogenous Vpr plays in HIV-associated central nervous system dysfunction, primary human fetal astrocytes were exposed to recombinant Vpr and a time- and dose-dependent decrease was demonstrated in two fundamental intracellular metabolites (ATP and glutathione (GSH)). Additionally, exposure to exogenous Vpr led to increased caspase activity and secretion of proinflammatory cytokines IL-6 and IL-8 and chemoattractants, monocyte chemotactic protein-1 and migration inhibition factor. Extracellular Vpr also dampened the glycolytic pathway through impairment of GAPDH activity, causing a decline in the levels of ATP. The reduction in intracellular ATP increased reactive oxygen species buildup, decreasing GSH concentrations, which affected several genes in the oxidative stress pathway. In addition, exposure of the SK-N-SH neuroblastoma cell line to conditioned medium from exogenous Vpr-treated astrocytes decreased synthesis of GSH, leading to their apoptosis. These observations point to a role that Vpr plays in altering astrocytic metabolism and indirectly affecting neuronal survival. We propose a model that may explain some of the neurological damage and therefore neurocognitive impairment observed during the course of HIV-1 disease.
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影响因子：
3.3
作者：
Chabory, E.;Damon, C.;Drevet, J. R.
通讯作者：
Drevet, J. R.
影响因子：
2.2
作者：
Lassiter, Coy;Fan, Xian;Joshi, Pratibha C;Jacob, Barbara A;Sutliff, Roy L;Jones, Dean P;Koval, Michael;Guidot, David M
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Guidot, David M
影响因子：
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作者：
Acharjee, Shaona;Noorbakhsh, Farshid;Power, Christopher
通讯作者：
Power, Christopher
影响因子：
3.1
作者：
Cheng, Xiandong;Mukhtar, Muhammad;Parveen, Zahida
通讯作者：
Parveen, Zahida
影响因子：
9.9
作者：
Cysique, L. A.;Vaida, F.;Ellis, R. J.
通讯作者：
Ellis, R. J.