Human immunodeficiency virus type 1 Vpr inhibits axonal outgrowth through induction of mitochondrial dysfunction
Human immunodeficiency virus type 1 Vpr inhibits axonal outgrowth through induction of mitochondrial dysfunction
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DOI：
10.1128/jvi.02094-07
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发表时间：
2008-03-01
影响因子：
5.4
通讯作者：
Koyanagi, Yoshio
中科院分区：
文献类型：
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作者：
Kitayama, Hiroko;Miura, Yoshiharu;Koyanagi, Yoshio
人类免疫缺陷病毒1型（HIV-1）感染的巨噬细胞会损害大脑中的成熟神经元，尽管它们对神经元发育的影响尚未阐明。在这项研究中，我们表明，HIV-1感染的巨噬细胞产生的因素，损害神经元前体细胞的发展和可溶性病毒蛋白R（Vpr）是有能力抑制轴突生长的因素之一。细胞生物学分析表明，细胞外施用的重组Vpr（rVpr）明显积累在线粒体中的Vpr结合蛋白腺嘌呤核苷酸转运定位，也降低了线粒体膜电位，从而导致ATP的合成。ATP合成的耗竭减少了神经突内线粒体的运输。这种线粒体功能障碍抑制轴突生长，即使当细胞凋亡的频率是不显着的。我们还发现，在位置73、77和80处精氨酸（R）残基至丙氨酸（A）残基的点突变使得rVpr不能引起线粒体膜去极化和轴突生长抑制。此外，Vpr诱导的抑制抑制后，治疗与泛醌类似物（泛醌-10）。我们的研究结果表明，可溶性Vpr是一个主要的病毒因子，通过诱导线粒体功能障碍引起神经元发育障碍。由于泛醌-10在体外保护神经元的可塑性，它可能是一种治疗剂，可以提供对HIV-1相关的神经系统疾病的防御。
Human immunodeficiency virus type 1 (HIV-1)-infected macrophages damage mature neurons in the brain, although their effect on neuronal development has not been clarified. In this study, we show that HIV-1-infected macrophages produce factors that impair the development of neuronal precursor cells and that soluble viral protein R (Vpr) is one of the factors that has the ability to suppress axonal growth. Cell biological analysis revealed that extracellularly administered recombinant Vpr (rVpr) clearly accumulated in mitochondria where a Vpr-binding protein adenine nucleotide translocator localizes and also decreased the mitochondrial membrane potential, which led to ATP synthesis. The depletion of ATP synthesis reduced the transportation of mitochondria within neurites. This mitochondrial dysfunction inhibited axonal growth even when the frequency of apoptosis was not significant. We also found that point mutations of arginine (R) residues to alanine (A) residues at positions 73, 77, and 80 rendered rVpr incapable of causing mitochondrial membrane depolarization and axonal growth inhibition. Moreover, the Vpr-induced inhibition was suppressed after treatment with a ubiquinone analogue (ubiquinone-10). Our results suggest that soluble Vpr is a major viral factor that causes a disturbance in neuronal development through the induction of mitochondrial dysfunction. Since ubiquinone-10 protects the neuronal plasticity in vitro, it may be a therapeutic agent that can offer defense against HIV-1-associated neurological disease.