State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433, China.
Mol Biol Rep. 2011 Nov;38(8):5071-8. doi: 10.1007/s11033-010-0653-6. Epub 2010 Dec 23.
HIV-1 latency represents a major problem in the eradication of HIV-1 in infected individuals treated with highly active anti-retroviral therapy. Histone deacetylase (HDAC) inhibits HIV-1 gene expression and virus production and may contribute to quiescence of HIV-1 within resting CD4+ T cells. Here, we evaluated the effect of Oxamflatin, a class I HDAC inhibitor, on the epigenetic change at HIV-1 long terminal repeat (LTR) and the induction of the latent viruses in the latency Jurkat T cell line. Flow cytometry assay showed that Oxamflatin activate HIV-1 gene expression in these latently infected cells by 2-17 fold than background levels. Chromatin immunoprecipitation (ChIP) assays further revealed that Oxamflatin increase the acetylation level of histone H3 and histone H4 at the nucleosome 1(nuc-1) site of the HIV-1 LTR compared to mock treatment. We also found that Oxamflatin had a synergization with prostratin, or 5-azacytidine or tumor necrosis factor-α to activate the HIV-1 promoter. Taken together, our results suggest that the histone acetylation plays an important role in regulating HIV-1 LTR gene expression, and Oxamflatin has potential as drug candidates as antilatency therapies.
HIV-1 潜伏期是接受高效抗逆转录病毒治疗的感染者中清除 HIV-1 的主要问题。组蛋白去乙酰化酶（HDAC）抑制 HIV-1 基因表达和病毒产生，并可能有助于静止的 CD4+T 细胞中 HIV-1 的休眠。在这里，我们评估了 Oxamflatin（一种 I 类 HDAC 抑制剂）对 HIV-1 长末端重复（LTR）的表观遗传变化以及潜伏 Jurkat T 细胞系中潜伏病毒的诱导作用。流式细胞术检测表明，Oxamflatin 比背景水平激活这些潜伏感染细胞中 HIV-1 基因表达 2-17 倍。染色质免疫沉淀（ChIP）实验进一步表明，与模拟处理相比，Oxamflatin 增加了 HIV-1 LTR 核小体 1（nuc-1）位点组蛋白 H3 和组蛋白 H4 的乙酰化水平。我们还发现，Oxamflatin 与 prostratin、5-氮杂胞苷或肿瘤坏死因子-α具有协同作用，可激活 HIV-1 启动子。总之，我们的结果表明，组蛋白乙酰化在调节 HIV-1 LTR 基因表达中起重要作用，Oxamflatin 具有作为抗潜伏治疗候选药物的潜力。
