Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is organised into minichromosomes by histone and non-histone proteins. Remodelling of minichromosomes is crucial for the regulation of HBV replication, which is dependent on the presence of the hepatitis B virus X protein (HBx). However, the mechanisms of HBx-dependent HBV replication remain obscure. The objective of this study was to investigate the mechanism of HBx-dependent HBV replication through the pathway of chromatin remodelling. The role of HBx was investigated by transfecting human HepG2 cells with the linear full-length HBV genome (wild-type) or HBx-deficient mutant HBV DNA (HBx mutant). Our results showed that although the formation of cccDNA was not affected by HBx, HBV replication, transcription and antigen secretion were all significantly reduced, resulting from the absence of HBx. The acetylation, mono-methylation and phosphorylation of cccDNA-bound histone H3 were associated with HBV replication. In addition, the levels of cccDNA-bound methylated, phosphorylated and acetylated histone H3 decreased sharply in HBx mutant HBV DNA. HBx modulated not only the status of acetylation but also the methylation and phosphorylation of histone H3 bound to the cccDNA during HBV replication in HepG2 cells. These findings suggest that HBx plays an important role in modulating the remodelling of minichromosomes related to HBV replication and it may regulate viral replication through the pathway of chromatin remodelling.

译文

乙型肝炎病毒(HBV)共价闭合的环状DNA(cccDNA)由组蛋白和非组蛋白组成微染色体。微染色体的重塑对于调节HBV复制至关重要,这取决于乙型肝炎病毒X蛋白(HBx)的存在。但是,依赖HBx的HBV复制的机制仍然不清楚。这项研究的目的是通过染色质重塑途径研究HBx依赖性HBV复制的机制。通过用线性全长HBV基因组(野生型)或HBx缺陷型突变HBV DNA(HBx突变体)转染人类HepG2细胞来研究HBx的作用。我们的结果表明,尽管ccx的形成不受ccx的影响,但由于不存在HBx,HBV复制,转录和抗原分泌均显着降低。 cccDNA结合的组蛋白H3的乙酰化,单甲基化和磷酸化与HBV复制有关。此外,在HBx突变体HBV DNA中,与cccDNA结合的甲基化,磷酸化和乙酰化组蛋白H3的水平急剧下降。 HBx不仅可以调节HBcc在HepG2细胞中复制时与cccDNA结合的组蛋白H3的乙酰化状态,而且可以调节其乙酰化状态。这些发现表明,HBx在调节与HBV复制有关的微染色体的重塑中起着重要作用,并且它可能通过染色质重塑的途径调节病毒的复制。

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