Infection with human immunodeficiency virus type 1 upregulates DNA methyltransferase, resulting in de novo methylation of the gamma interferon (IFN-γ) promoter and subsequent downregulation of IFN-γ production
Infection with human immunodeficiency virus type 1 upregulates DNA methyltransferase, resulting in de novo methylation of the gamma interferon (IFN-γ) promoter and subsequent downregulation of IFN-γ production
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DOI：
10.1128/mcb.18.9.5166
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发表时间：
1998-09-01
影响因子：
5.3
通讯作者：
Ruscetti, FW
中科院分区：
文献类型：
--
作者：
Mikovits, JA;Young, HA;Ruscetti, FW
对病原体的免疫反应是由细胞因子的微妙平衡调节的。人类逆转录病毒感染后，细胞因子基因表达的失调，包括白细胞介素-12肿瘤坏死因子α和γ干扰素（ifn - γ）。这种基因表达可能被调节的一个过程是DNA甲基化的改变。在辅助性t细胞亚群中，ifn - γ（一种对病毒感染的免疫反应很重要的细胞因子）的表达部分受DNA甲基化调节，因此mRNA的表达与启动子的甲基化状态呈负相关。在许多甲基化状态可能受病毒感染影响的基因中，我们将ifn - γ基因作为候选基因进行了研究。我们在这里表明，人类免疫缺陷病毒1型（HIV 1）细胞的急性感染导致(i) DNA甲基转移酶的表达和活性增加，（ii）感染细胞中DNA甲基化的总体增加，以及（iii） ifn - γ基因启动子中CpG二核苷酸的重新甲基化，导致随后该细胞因子的表达下调。在淋巴细胞中引入反义甲基转移酶结构导致甲基转移酶表达显著降低，整个ifn - γ基因的低甲基化，并增加ifn - γ的产生，这表明甲基转移酶与ifn - γ基因表达之间存在直接联系。DNA甲基转移酶活性增加下调ifn - γ基因等基因表达的能力可能是hiv -1感染个体中T细胞功能障碍的机制之一。
The immune response to pathogens is regulated by a delicate balance of cytokines. The dysregulation of cytokine gene expression, including interleukin-12 tumor necrosis factor alpha, and gamma interferon (IFN-gamma), following human retrovirus infection is well documented. One process by which such gene expression may be modulated is altered DNA methylation. In subsets of T-helper cells, the expression of IFN-gamma, a cytokine important to the immune response to viral infection, is regulated in part by DNA methylation such that mRNA expression inversely correlates with the methylation status of the promoter. Of the many possible genes whose methylation status could be affected by viral infection, we examined the IFN-gamma gene as a candidate. We show here that acute infection of cells with human immunodeficiency virus type 1 (HIV 1) results in (i) increased DNA methyltransferase expression and activity, (ii) an overall increase in methylation of DNA in infected cells, and (iii) the de novo methylation of a CpG dinucleotide in the IFN-gamma gene promoter, resulting in the subsequent downregulation of expression of this cytokine. The introduction of an antisense methyltransferase construct into lymphoid cells resulted in markedly decreased methyltransferase expression, hypomethylation throughout the IFN-gamma gene, and increased IFN-gamma production, demonstrating a direct link between methyltransferase and IFN-gamma gene expression. The ability of increased DNA methyltransferase activity to downregulate the expression of genes like the IFN-gamma gene may be one of the mechanisms for dysfunction of T cells in HIV-1-infected individuals.