Differential Induction of Rat Neuronal Excitotoxic Cell Death by Human Immunodeficiency Virus Type 1 Clade B and C Tat Proteins
Differential Induction of Rat Neuronal Excitotoxic Cell Death by Human Immunodeficiency Virus Type 1 Clade B and C Tat Proteins
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DOI：
10.1089/aid.2010.0192
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发表时间：
2011-06-01
影响因子：
1.5
通讯作者：
Spector, Stephen A.
中科院分区：
文献类型：
--
作者：
Campbell, Grant R.;Watkins, Jennifer D.;Spector, Stephen A.
在缺乏有效的抗逆转录病毒治疗的情况下，感染进化枝B人类免疫缺陷病毒（HIV-1）感染通常进展为AIDS痴呆。然而，在印度，其中C分支感染是最普遍的，严重的认知障碍，由于艾滋病毒-1据报道不太普遍。HIV-1的达特蛋白是从HIV-1感染的巨噬细胞释放的，被认为在神经元功能的破坏以及与晚期神经发病相关的巨噬细胞浸润中起主要作用。进化枝B达特通过锌结合依赖性机制增强锌敏感性NR 1/NR 2A N-甲基-D-天冬氨酸受体的N-甲基-D-天冬氨酸诱导电流，对海马神经元具有兴奋性毒性。本研究的特点是锌结合特性的进化枝C达特蛋白。使用紫外光谱和Ellman反应，我们表明，进化枝C达特蛋白结合每个单体只有一个锌离子。然后，我们研究了进化枝C达特通过离子螯合作用阻断锌拮抗作用对N-甲基-D-天冬氨酸受体的抑制的能力。虽然进化枝C达特增强N-甲基-D-天冬氨酸介导的大鼠海马神经元毒性的锌的存在下，增加显着小于观察到的进化枝B达特。这些研究结果表明，观察到的差异，发现与HIV-1进化枝C感染相比，进化枝B的神经发病机制，可能是由于减少了Tat介导的神经毒性。
In the absence of effective antiretroviral therapy, infection with clade B human immunodeficiency virus (HIV-1) infection commonly progresses to AIDS dementia. However, in India, where clade C infection is most prevalent, severe cognitive impairment due to HIV-1 is reported to be less prevalent. The Tat protein of HIV-1, which is released from HIV-1-infected macrophages, is thought to play a major role in the disruption of neuronal function as well as in the infiltration of macrophages associated with advanced neuropathogenesis. Clade B Tat is excitotoxic to hippocampal neurons by potentiating N-methyl-D-aspartate-induced currents of the zinc-sensitive NR1/NR2A N-methyl-D-aspartate receptor in a zinc-binding-dependent mechanism. This study characterizes the zinc-binding properties of clade C Tat protein. Using ultraviolet spectroscopy and the Ellman reaction, we show that clade C Tat protein binds just one zinc ion per monomer. We then investigated the ability of clade C Tat to block the inhibition of N-methyl-D-aspartate receptors from zinc antagonism through ion chelation. Although clade C Tat enhanced N-methyl-D-aspartate-mediated rat hippocampus neuronal toxicity in the presence of zinc, the increase was significantly less than that observed with clade B Tat. These findings suggest that the observed differences in neuropathogenesis found with HIV-1 clade C infection compared to clade B may, in part, be due to a decrease in Tat-mediated neurotoxicity.