The mechanism of natural occurrence of two closely linked HBV precore predominant mutations.
The mechanism of natural occurrence of two closely linked HBV precore predominant mutations.
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两种密切相关的 HBV 前核心显性突变自然发生的机制。
DOI：
10.1006/viro.1995.1387
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发表时间：
1995
期刊：
影响因子：
--
通讯作者：
Shih,C
中科院分区：
文献类型：
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作者：
Yuan,TT;Faruqi,A;Shih,JW;Shih,C
人B型肝炎病毒（HBV）核苷酸1896或1899位的两个前C区优势突变常同时发生。在nt 1896处，G至A突变在前核心蛋白的密码子28处产生TAG终止密码子。在nt 1899处，G至A突变将密码子29处的甘氨酸改变为天冬氨酸。为了评估每个单独突变的影响以及这两个突变之间的任何相互作用，已经构建了携带一个或两个前核心主导突变的HBV衍生物。在密码子28处携带TAG终止密码子突变的HBV e-Ag阴性突变体的复制均匀地比在相同氨基酸位置处携带TGA终止密码子的突变体好至少20倍，而与nt 1899处的序列背景无关。在nt 1699处的单个突变，将野生型G改变为嘧啶（T或C），对病毒RNA聚合和DNA复制有害。我们的研究结果部分解释了为什么在天然HBV基因组中只观察到nt 1699处的嘌呤（G或A），而不是嘧啶。这两个紧密相连的突变对重要复制的影响并非相互独立。严格选择一个高效的RNA双核苷化元件可能在这两个紧密相连的前核心突变的自然发生中起着至关重要的作用。由nt 1896突变截短前核心产生的推定的27个氨基酸的肽对病毒复制没有明显的影响。优先发生的G到A突变在核苷酸1896和1899，而不是在其他非优势位置，可能是一个综合的结果，选择和更高的内在突变频率在这些位置。
Two precore predominant mutations of human hepatitis B virus (HBV) at either nucleotide (nt) 1896 or nt 1899 often occur in combination. At nt 1896, a G to A mutation creates a TAG stop codon at codon 28 of precore protein. At nt 1899, a G to A mutation changes glycine at codon 29 to aspartic acid. To assess the effect of each individual mutation as well as any interaction between these two mutations, HBV derivatives bearing one or both precore predominant mutations have been constructed. HBV e-Ag-negative mutants bearing a TAG stop codon mutation at codon 28 uniformly replicate at least 20-fold better than mutants bearing a TGA stop codon at the same amino acid position, irrespective of the sequence context at nt 1899. A single mutation at nt 1699, changing the wild-type G to a pyrimidine (T or C) is deleterious to viral RNA encapsidation and DNA replication. Our results explain in part why only a purina (G or A) at nt 1699, never a pyrimidine, is observed in natural HBV genomes. The effects caused by these two closely linked mutations on vital replication are not independent of each other. The stringent selection for a highly efficient RNA encapsidation element may play a crucial role in the natural occurrence of these two closely linked precore mutations. The putative 27-amino-acid peptide resulting from the truncation of precore by the nt 1896 mutation has no apparent effect on viral replication. The preferential occurrence of the G to A mutation at nt 1896 and 1899, instead of at other nonpredominant positions, is likely to be a combined consequence of both selection and higher intrinsic mutation frequency at these positions.