HEPATITIS-B VIRUS GENOTYPE-A RARELY CIRCULATES AS AN HBE-MINUS MUTANT - POSSIBLE CONTRIBUTION OF A SINGLE NUCLEOTIDE IN THE PRECORE REGION
HEPATITIS-B VIRUS GENOTYPE-A RARELY CIRCULATES AS AN HBE-MINUS MUTANT - POSSIBLE CONTRIBUTION OF A SINGLE NUCLEOTIDE IN THE PRECORE REGION
复制标题
DOI：
10.1128/jvi.67.9.5402-5410.1993
复制
发表时间：
1993-09-01
影响因子：
5.4
通讯作者：
TREPO, C
中科院分区：
文献类型：
--
作者：
LI, JS;TONG, SP;TREPO, C
无HBe的B型肝炎病毒（HBV）突变体的出现，通常通过前C区密码子28处的UAG无义突变，帮助病毒在宿主的抗HBe免疫应答中存活。宿主和病毒因素，易患这种突变体的出现没有得到很好的表征。前C区形成病毒前基因组RNA包装所必需的发夹结构的事实可以解释密码子28处UAG突变的极高发生率。它将包装信号中密码子15的核苷酸3（CCU）和密码子28的核苷酸2（UGG）之间的摆动U-G对转化为U-A对。由于HBV基因型A在密码子15处具有CCC序列，因此UAG突变反而会破坏野生型病毒中存在的C-G对。转染实验表明，这种改变大大损害了前基因组RNA的包装。分子流行病学研究阐明了这一发现的意义。基因型A被认为是法国野生型病毒群体中最普遍的基因型，但在那里发现的46株HBe-阴性突变株中仅发现1株。这些突变体主要由基因型D贡献，基因型D是法国第二大流行基因型，其特征在于密码子15处的CCU序列。密码子15处的单核苷酸的作用通过发现其中存在野生型和突变型病毒的单个基因型A分离株而得到证实。有趣的是，几乎所有的突变体都具有CCU的密码子15序列，而不是野生型病毒中存在的CCC。我们的研究结果表明，HBV基因型A很少作为HBe-减突变体循环，可能是因为需要在密码子15处同时发生序列变化。这些数据，加上中国样本中几乎没有基因型A，可能会提供一些见解，在世界各地的不均衡流行的HBe-负突变体。
The emergence of HBe-minus hepatitis B virus (HBV) mutants, usually through a UAG nonsense mutation at codon 28 of the precore region, helps the virus to survive the anti-HBe immune response of the host. Host and viral factors that predispose to the emergence of such mutants are not well characterized. The fact that the precore region forms a hairpin structure essential for the packaging of viral pregenomic RNA may explain the extremely high prevalence of the UAG mutation at codon 28. It converts a wobble U-G pair in the packaging signal between nucleotide 3 of codon 15 (CCU) and nucleotide 2 of codon 28 (UGG) into a U-A pair. Since genotype A of HBV has a CCC sequence at codon 15, the UAG mutation would, instead, disrupt a C-G pair present in the wild-type virus. This alteration was shown by transfection experiments to greatly compromise the packaging of pregenomic RNA. The implication of this finding was elucidated by molecular epidemiological studies. Genotype A was found to be the most prevalent genotype in the wild-type vims populations in France but was found in only 1 of the 46 isolates of HBe-minus mutants found there. These mutants were contributed chiefly by genotype D, the second most prevalent genotype in France, which is characterized by a CCU sequence at codon 15. The role of the single nucleotide at codon 15 was confirmed by the finding of the single genotype A isolate in which both wild-type and mutant viruses were present. Interestingly, nearly all of the mutants had a codon 15 sequence of CCU instead of the CCC present in the wild-type viruses. Our results suggest that genotype A of HBV rarely circulates as HBe-minus mutants, probably because of a requirement for a simultaneous sequence change at codon 15. These data, together with the virtual absence of genotype A in the Chinese samples examined, may provide some insights into the uneven prevalence of HBe-minus mutants in the world.