Clade-specific differences in neurotoxicity of human immunodeficiency virus-1 B and C tat of human neurons: Significance of dicysteine C30C31 motif
Clade-specific differences in neurotoxicity of human immunodeficiency virus-1 B and C tat of human neurons: Significance of dicysteine C30C31 motif
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DOI：
10.1002/ana.21292
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发表时间：
2008-03-01
影响因子：
11.2
通讯作者：
Seth, Pankaj
中科院分区：
文献类型：
--
作者：
Mishra, Mamara;Vetrivel, S.;Seth, Pankaj
目的：人类免疫缺陷病毒-1 （HIV-1）可导致轻度至重度认知障碍和痴呆。反激活病毒蛋白Tat与神经功能缺陷引起的神经元死亡有关。HIV-1的几个分支在全球分布不均，其中HIV-1 B和C共同占大多数病毒感染。hiv -1相关的神经功能缺陷似乎在B支最常见，而在C支流行区域则不常见。分支特异性差异是否转化为不同的神经发病机制尚不清楚，这种不确定性要求立即研究来自不同病毒分支的Tat对人类神经元的神经毒性。方法：利用人胎儿中枢神经系统祖细胞来源的星形胶质细胞和神经元，研究B-和C-Tat通过直接和间接损伤人神经元对神经元细胞死亡、趋化因子分泌、氧化应激和线粒体膜去极化的影响。我们使用Tat的等基因变异来深入了解Tat的半胱氨酸基序（0001）在神经毒性潜能中的作用。结果：我们的研究结果表明，tat诱导的人原代神经元凋亡在枝特异性功能上存在差异。这项研究表明，与B-Tat相比，C-Tat的神经毒性相对较小，这可能是由于B-Tat神经毒性区域内的半胱氨酸基序发生了改变。解释：这项研究为B-和C-Tar的不同神经毒性特性提供了重要见解，并为在印度患者中观察到的hiv -1相关神经功能缺陷程度的明显差异提供了基础。需要进一步的患者样本研究来验证这些发现。
Objective: Human immunodeficiency virus-1 (HIV-1) causes mild to severe cognitive impairment and dementia. The transactivator viral protein, Tat, is implicated in neuronal death responsible for neurological deficits. Several clades of HIV-1 are unequally distributed globally, of which HIV-1 B and C together account for the majority of the viral infections. HIV-1-related neurological deficits appear to be most common in clade B, but not clade C prevalent areas. Whether clade-specific differences , translate to varied neuropathogenesis is not known, and this uncertainty warrants an immediate investigation into neurotoxicity on human neurons of Tat derived from different viral clades.Methods: We used human fetal central nervous system progenitor cell-derived astrocytes and neurons to investigate effects of B- and C-Tat on neuronal cell death, chemokine secretion, oxidative stress, and mitochondrial membrane depolarization by direct and indirect damage to human neurons. We used isogenic variants of Tat to gain insights into the role of the dicysteine motif (0001) for neurotoxic potential of Tat.Results: Our results suggest clade-specific functional differences in Tat-induced apoptosis in primary human neurons. This study demonstrates that C-Tat is relatively less neurotoxic compared with B-Tat, probably as a result of alteration in the dicysteine motif within the neurotoxic region of B-Tat.Interpretation: This study provides important insights into differential neurotoxic properties of B- and C-Tar, and offers a basis for distinct differences in degree of HIV-1-associated neurological deficits observed in patients in India. Additional studies with patient samples are necessary to validate these findings.