Abstract：
HIV-associated neurocognitive disorders (HAND) remain pervasive even with increased efficacy/use of antiretroviral therapies. Opioid use/abuse among HIV + individuals is documented to exacerbate CNS deficits. White matter (WM) alterations, including myelin pallor, and volume/structural alterations detected by diffusion tensor imaging are common observations in HIV + individuals, and studies in non-human primates suggest that WM may harbor virus. Using transgenic mice that express the HIV-1 Tat protein, we examined in vivo effects of 2-6 weeks of Tat and morphine exposure on WM using genomic and biochemical methods. RNA sequencing of striatal tissue at 2 weeks revealed robust changes in mRNAs associated with oligodendrocyte precursor populations and myelin integrity, including those for transferrin, the atypical oligodendrocyte marker N-myc downstream regulated 1 (Ndrg1), and myelin regulatory factor (Myrf/Mrf), an oligodendrocyte-specific transcription factor with a significant role in oligodendrocyte differentiation/maturation. Western blots conducted after 6-weeks exposure in 3 brain regions (striatum, corpus callosum, pre-frontal cortex) revealed regional differences in the effect of Tat and morphine on Myrf levels, and on levels of myelin basic protein (MBP), whose transcription is regulated by Myrf. Responses included individual and interactive effects. Although baseline and post-treatment levels of Myrf and MBP differed between brain regions, post-treatment MBP levels in striatum and pre-frontal cortex were compatible with changes in Myrf activity. Additionally, the Myrf regulatory ubiquitin ligase Fbxw7 was identified as a novel target in our model. These results suggest that Myrf and Fbxw7 contribute to altered myelin gene regulation in HIV.
摘要：
HIV相关的神经认知障碍（HAND）即使增加了抗逆转录病毒疗法的疗效/使用，也仍然普遍存在。据记载，在HIV+个体中使用/滥用阿片类药物会加剧CNS缺陷。白质（WM）改变，包括髓鞘苍白，扩散张量成像检测到的体积/结构改变是HIV+个体的常见观察结果，在非人类灵长类动物中的研究表明，WM可能带有病毒。使用表达HIV-1Tat蛋白的转基因小鼠，我们使用基因组和生化方法检查了2-6周Tat和吗啡暴露对WM的体内影响。2周时纹状体组织的RNA测序显示，与少突胶质细胞前体群体和髓磷脂完整性相关的mRNA发生了强烈变化。包括转铁蛋白，非典型少突胶质细胞标记N-myc下游调节1(Ndrg1)，和髓鞘调节因子（Myrf/Mrf），在少突胶质细胞分化/成熟中具有重要作用的少突胶质细胞特异性转录因子。在3个脑区暴露6周后进行的Western印迹（纹状体，call体,前额叶皮质）揭示了Tat和吗啡对Myrf水平的影响的区域差异，和髓鞘碱性蛋白（MBP）的水平，其转录受Myrf调控。反应包括个人和互动效果。尽管Myrf和MBP的基线和治疗后水平在大脑区域之间有所不同，治疗后纹状体和前额叶皮质的MBP水平与Myrf活性的变化相一致。此外,Myrf调节泛素连接酶Fbxw7在我们的模型中被确定为新的靶标。这些结果表明Myrf和Fbxw7有助于改变HIV中的髓磷脂基因调控。
