Novel type of hepatitis B virus mutation: Replacement mutation involving a hepatocyte nuclear factor 1 binding site tandem repeat in chronic hepatitis B virus genotype E
Novel type of hepatitis B virus mutation: Replacement mutation involving a hepatocyte nuclear factor 1 binding site tandem repeat in chronic hepatitis B virus genotype E
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DOI：
10.1128/jvi.79.22.14404-14410.2005
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发表时间：
2005-11-01
影响因子：
5.4
通讯作者：
Naoumov, NV
中科院分区：
文献类型：
--
作者：
Fujiwara, K;Tanaka, Y;Naoumov, NV
B型肝炎病毒（HBV）株的遗传多样性通过突变如点突变、缺失或插入以及重组而进化。我们发现并表征了一种新的突变类型，它是一个复杂的外部插入，缺失，和内部重复序列从6例慢性肝炎B病毒基因型E（HBV/E）。我们暂时将这种突变命名为“替换突变”;核心启动子上游调控序列/基本核心启动子被替换为覆盖肝细胞核因子1（HNF 1）结合位点的SI启动子的一部分，随后是HNF 1位点的串联重复。对HBV人群6年的纵向分析显示，从野生型HBV/E到复制突变型的克隆变化，导致B（HB）e抗原滴度降低，血清中HBV DNA水平升高，肝纤维化进展。在一项使用复制模型的体外研究中，复制突变型HBV显示出比野生型HBV/E复制子更高的复制水平，这可能是由改变的转录因子结合介导的。此外，在体内和体外研究中，该HNF 1位点置换突变与肝细胞中HB核衣壳蛋白过度表达相关。这种新的突变可能是特定的HBV基因型E，其患病率需要进一步调查。
The genetic diversity of hepatitis B virus (HBV) strains has evolved through mutations such as point mutations, deletions or insertions, and recombination. We identified and characterized a novel type of mutation which is a complex of external insertion, deletion, and internal duplication in sequences from one of six patients with chronic hepatitis B virus genotype E (HBV/E). We provisionally named this mutation a "replacement mutation"; the core promoter upstream regulatory sequence/basic core promoter was replaced with a part of the SI promoter covering the hepatocyte nuclear factor 1 (HNF1) binding site, followed by a tandem repeat of the HNF1 site. A longitudinal analysis of the HBV population over 6 years showed the clonal change from wild-type HBV/E to replacement-mutant type, resulting in a lower hepatitis B (HB) e antigen titer, a high HBV DNA level in serum, and progression of liver fibrosis. In an in vitro study using a replication model, the replacement-mutant HBV showed higher replication levels than the wild-type HBV/E replicon, probably mediated by altered transcription factor binding. Additionally, this HNF1 site replacement mutation was associated with excessive HB nucleocapsid protein expression in hepatocytes, in both in vivo and in vitro studies. This novel mutation may be specific to HBV genotype E, and its prevalence requires further investigation.