IFN-α inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome
IFN-α inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome
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DOI：
10.1172/jci58847
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发表时间：
2012-02-01
影响因子：
15.9
通讯作者：
Levrero, Massimo
中科院分区：
文献类型：
--
作者：
Belloni, Laura;Allweiss, Lena;Levrero, Massimo
HBV感染仍然是全球死亡的主要原因。IFN-α在体外和体内抑制病毒复制，并且聚乙二醇化IFN-α是感染HBV的个体的常用给药治疗。HBV基因组含有典型的IFN刺激反应元件（ISRE），但IFN-α抑制HBV复制的分子机制尚未在相关实验系统中建立。在这里，我们表明IFN-α通过减少前基因组RNA（pgRNA）和HBV共价闭合环状DNA（cccDNA）微型染色体的亚基因组RNA的转录来抑制HBV复制，无论是在HBV复制的培养细胞中，还是在肝脏已被人肝细胞重新填充并感染HBV的小鼠中。IFN-α的施用导致cccDNA结合的组蛋白低乙酰化以及转录辅阻遏物向cccDNA的主动募集。IFN-α处理还减少了STAT 1和STAT 2转录因子与活性cccDNA的结合。IFN-α的抑制活性与IRSE有关，因为IRSE突变型HBV转录较少的pgRNA，并且不能被IFN-α处理抑制。我们的研究结果确定了IFN-α介导HBV cccDNA转录活性的表观遗传抑制的分子机制，这可能有助于开发新的有效治疗方法。
HBV infection remains a leading cause of death worldwide. IFN-alpha inhibits viral replication in vitro and in vivo, and pegylated IFN-alpha is a commonly administered treatment for individuals infected with HBV. The HBV genome contains a typical IFN-stimulated response element (ISRE), but the molecular mechanisms by which IFN-alpha suppresses HBV replication have not been established in relevant experimental systems. Here, we show that IFN-alpha inhibits HBV replication by decreasing the transcription of pregenomic RNA (pgRNA) and sub-genomic RNA from the HBV covalently closed circular DNA (cccDNA) minichromosome, both in cultured cells in which HBV is replicating and in mice whose livers have been repopulated with human hepatocytes and infected with HBV. Administration of IFN-alpha resulted in cccDNA-bound histone hypoacetylation as well as active recruitment to the cccDNA of transcriptional corepressors. IFN-alpha treatment also reduced binding of the STAT1 and STAT2 transcription factors to active cccDNA. The inhibitory activity of IFN-alpha was linked to the IRSE, as IRSE-mutant HBV transcribed less pgRNA and could not be repressed by IFN-alpha treatment. Our results identify a molecular mechanism whereby IFN-alpha mediates epigenetic repression of HBV cccDNA transcriptional activity, which may assist in the development of novel effective therapeutics.