Effects of a naturally occurring mutation in the hepatitis B virus basal core promoter on precore gene expression and viral replication
Effects of a naturally occurring mutation in the hepatitis B virus basal core promoter on precore gene expression and viral replication
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DOI：
10.1128/jvi.70.9.5845-5851.1996
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发表时间：
1996-09-01
影响因子：
5.4
通讯作者：
Ou, JH
中科院分区：
文献类型：
--
作者：
Buckwold, VE;Xu, ZC;Ou, JH
乙肝病毒基本核心启动子(BCP)控制前C区和核心区的转录，前C区编码分泌的e抗原，而核心区编码主要核心蛋白和DNA聚合酶，同时也是前基因组RNA。在从慢性患者分离的乙肝病毒序列中，经常发现BCP中的1762和1764位核苷酸分别从A和G双突变为T和A，关于这一双突变是否对e抗原的表达起重要作用，已有几篇文献报道了相互矛盾的结果。为了解决这一问题，我们将这一双突变引入到乙肝病毒基因组中，并研究了其对乙肝病毒基因表达和复制的影响。我们的结果表明，突变的BCP不再与肝脏富集型转录因子S结合，而只是转录前C区核糖核酸，从而减少了e抗原的表达。前C基因表达的降低伴随着子代病毒产量的增加。这种增加被发现发生在前基因组RNA被包裹的时候或之前。因此，我们的体外研究结果解决了以往临床观察的差异，表明该双突变抑制但不取消e抗原表型，并讨论了这些发现在乙肝发病机制中的意义。
The basal core promoter (BCP) of hepatitis B virus (HBV) controls the transcription of both the precore RNA and the core RNA, The precore RNA codes for the secreted e antigen, while the core RNA codes for the major core protein and the DNA polymerase and also is the pregenomic RNA. The double mutation of nucleotides 1762 and 1764 in the BCP from A and G to T and A, respectively, is frequently observed in HBV sequences isolated from chronic patients, Several papers have reported conflicting results regarding whether this double mutation is important for e antigen expression, In order to address this issue, we have introduced this double mutation into the HBV genome and studied its effects on HBV gene expression and replication. Our results indicate that the mutated BCP can no longer bind a liver-enriched transcription factor(s) and that the transcription of only precore RNA and, consequently, the expression of e antigen were reduced. The reduction of precore gene expression was accompanied by an increase in progeny virus production. This increase was found to occur at or immediately prior to the encapsidation of the pregenomic RNA. Thus, the results of our in vitro study resolve the discrepancy of previous clinical observations and indicate that this double mutation suppresses but does not abolish the e antigen phenotype, The implications of these findings in the pathogenesis of HBV are discussed.