Discipline of Human Physiology, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.
Neurosci Res. 2012 Sep;74(1):59-63. doi: 10.1016/j.neures.2012.05.014. Epub 2012 Jun 12.
The HIV-1 transactivator protein tat is pivotal to the pathogenesis of AIDS, exerting its effects on both viral and cellular gene expression. The basic structure of tat protein allows it to be secreted by HIV-1 infected cells and penetrate uninfected cells where it elicits its multifunctional biochemical effects. The main function of tat protein is viral transactivation which leads to the upregulation of transcription through complex interactions with RNA and host cell factors. Since HIV-1 has been widely implicated as a causative agent of HIV-1 dementia, the aim of our study was to investigate the ability of two novel metal chelators, fusaric acid (FA) and picolinic acid (PA) to firstly inhibit HIV-1 tat induced transcription and secondly, to minimize its cytotoxic effects as mediated via apoptosis. Biologically active tat protein is not freely available commercially. We therefore had to produce, isolate and purify our own protein. A cell culture system and flow cytometric techniques were used in our study. Exposure of CEM-GFP cells to exogenous recombinant tat protein induced transcription and apoptosis, and both processes were inhibited by FA and PA at concentrations that alone did not induce any cytotoxicity. Our data suggest that FA and PA may have therapeutic potential in the management of HIV-1 dementia.
HIV-1 转录激活蛋白 tat 是艾滋病发病机制的关键，它对病毒和细胞基因表达都有影响。tat 蛋白的基本结构使其能够被 HIV-1 感染的细胞分泌，并穿透未感染的细胞，在那里引发其多功能生化效应。tat 蛋白的主要功能是病毒转录激活，通过与 RNA 和宿主细胞因子的复杂相互作用，导致转录的上调。由于 HIV-1 已被广泛认为是 HIV-1 痴呆的致病因素，我们的研究目的是研究两种新型金属螯合剂 Fusaric acid（FA）和 Picolinic acid（PA）的能力，首先抑制 HIV-1 tat 诱导的转录，其次，通过凋亡最小化其细胞毒性作用。生物活性 tat 蛋白在商业上不易获得。因此，我们必须自己生产、分离和纯化我们的蛋白。我们的研究使用了细胞培养系统和流式细胞术技术。外源性重组 tat 蛋白暴露于 CEM-GFP 细胞中会诱导转录和凋亡，而 FA 和 PA 可抑制这两个过程，且其浓度单独作用时不会引起任何细胞毒性。我们的数据表明，FA 和 PA 可能具有治疗 HIV-1 痴呆的潜力。
