HIV-1 Vpr potently induces programmed cell death in the CNS in vivo
HIV-1 Vpr potently induces programmed cell death in the CNS in vivo
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DOI：
10.1089/dna.2006.0541
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发表时间：
2007-02-01
影响因子：
3.1
通讯作者：
Parveen, Zahida
中科院分区：
文献类型：
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作者：
Cheng, Xiandong;Mukhtar, Muhammad;Parveen, Zahida
人类免疫缺陷病毒I型（HIV-1）辅助蛋白Vpr与诱导程序性细胞死亡（凋亡）和细胞周期停滞有关。研究已经显示Vpr对原代和已建立的细胞系以及对包括中枢神经系统（CNS）在内的多种组织的体外凋亡作用。然而，在体外观察到的Vpr对体内HIV-1神经发病机制的影响的相关性仍然未知。由于HIV-1感染的宿主范围较窄，目前还没有可用的动物模型。这促使我们考虑一个小动物模型，以评估Vpr对中枢神经系统在体内通过替代病毒表达HIV-1Vpr的影响。一轮的复制能力的病毒载体，表达Vpr，被用来研究HIV-1Vpr在体内的免疫诱导能力。用VSV-G或N2 c包膜假型化的病毒颗粒由脾坏死病毒（SNV）和基于HIV-1的载体产生，以接种CNS细胞。体外研究表明，与HIV-1载体表达的Vpr相比，SNV载体表达的Vpr对CNS细胞的凋亡作用较小。体内研究表明，表达由基于HIV-1的载体产生的Vpr的病毒颗粒，当通过心室递送时，引起皮质区域神经元和树突状突起的损失。细胞凋亡的影响超出了皮质区，影响海马神经元，脉络丛的衬里，和小脑。然而，Vpr的作用，当通过皮质传递时，仅在注射部位周围显示神经元损伤。有趣的是，表达Vpr的HIV-1载体的凋亡神经元的数量显著高于SNV载体。这可能是由于这些病毒载体表达的蛋白质的差异。这些结果表明，Vpr在体外和体内诱导CNS细胞凋亡。据我们所知，这是第一个研究HIV-1Vpr在新生小鼠体内诱导凋亡的能力的研究。我们建议，在昂贵的动物模型中，这可能对设计靶向神经保护疗法具有价值。
The human immunodeficiency virus type I (HIV-1) accessory protein Vpr has been associated with the induction of programmed cell death ( apoptosis) and cell-cycle arrest. Studies have shown the apoptotic effect of Vpr on primary and established cell lines and on diverse tissues including the central nervous system (CNS) in vitro. However, the relevance of the effect of Vpr observed in vitro to HIV-1 neuropathogenesis in vivo, remains unknown. Due to the narrow host range of HIV-1 infection, no animal model is currently available. This has prompted us to consider a small animal model to evaluate the effects of Vpr on CNS in vivo through surrogate viruses expressing HIV-1Vpr. A single round of replication competent viral vectors, expressing Vpr, were used to investigate the apoptosis-inducing capabilities of HIV-1Vpr in vivo. Viral particles pseudotyped with VSV-G or N2c envelopes were generated from spleen necrosis virus ( SNV) and HIV-1-based vectors to transduce CNS cells. The in vitro studies have demonstrated that Vpr generated by SNV vectors had less apoptotic effects on CNS cells compared with Vpr expressed by HIV-1 vectors. The in vivo study has suggested that viral particles, expressing Vpr generated by HIV-1-based vectors, when delivered through the ventricle, caused loss of neurons and dendritic processes in the cortical region. The apoptotic effect was extended beyond the cortical region and affected the hippocampus neurons, the lining of the choroids plexus, and the cerebellum. However, the effect of Vpr, when delivered through the cortex, showed neuronal damage only around the site of injection. Interestingly, the number of apoptotic neurons were significantly higher with HIV-1 vectors expressing Vpr than by the SNV vectors. This may be due to the differences in the proteins expressed by these viral vectors. These results suggest that Vpr induces apoptosis in CNS cells in vitro and in vivo. To our knowledge, this is the first study to investigate the apoptosis-inducing capabilities of HIV-1Vpr in vivo in neonatal mice. We propose that this, in expensive animal model, may be of value to design-targeted neuroprotective therapeutics.