Wu J C, Chiang T Y, Shiue W K, Wang S Y, Sheen I J, Huang Y H, Syu W J
Department of Medicine, Veterans General Hospital, Taipei, Taiwan.
Mol Biol Evol. 1999 Nov;16(11):1622-32. doi: 10.1093/oxfordjournals.molbev.a026075.
Recombination between RNA sequences plays a role in the fast evolution of a few viruses. There has been no report on hepatitis D virus (HDV) recombination. In this study, we analyzed genetic recombination of HDV and its possible impact on evolution and clinical course. The aligned HDV sequences allowed us to construct a phylogenetic tree which supported the notion of distinct lineages of HDV. The tree was also used in the analysis of recombination using partial likelihoods assessed through optimization. Nine segments of the HDV genome with significant levels of genetic recombination were detected. Five segments were in the hypervariable region, and four were in the delta-antigen- coding region. None could be found in the well-conserved autocleavage region that is essential for replication. Recombination occurred both between and within types. The results of this study indicated that the remarkable variation in HDV genomic sequences, particularly in the hypervariable region, among different genotypes may at least partly result from multiple episodes of genetic recombination during evolution. Genetic recombination may play a significant role in increasing genetic diversity. Importantly, a genetic recombination (nt 1082-1093) occurred in one of the immunogenic domains of hepatitis delta virus antigen recognized by human and woodchuck antibodies (amino acids 174-195). Genetic recombination also occurred at another segment between nt 1517 and 1535, which was close to one of the predicted T-cell epitopes (amino acids 26-41). In longitudinal analysis of HDV genomes at different time points during chronic infection, novel dominant HDV strains with amino acid changes at these epitopes usually emerged after severe hepatitis attacks. In the comparison of HDV clones during or shortly after flare-up of liver disease, Ka/Ks ratios of > 1 were frequently found, suggesting Darwinian positive selection. Therefore, recombination in these two segments may play an important role for HDV in the evasion of immunity.
RNA序列之间的重组在一些病毒的快速进化中发挥作用。目前尚无关于丁型肝炎病毒（HDV）重组的报道。在本研究中，我们分析了HDV的基因重组及其对进化和临床病程的可能影响。比对后的HDV序列使我们能够构建系统发育树，该树支持HDV不同谱系的概念。该树还用于通过优化评估的部分似然性进行重组分析。检测到HDV基因组的9个片段存在显著水平的基因重组。5个片段位于高变区，4个位于δ抗原编码区。在对复制至关重要的保守自切割区未发现重组。重组发生在不同类型之间以及同一类型内部。本研究结果表明，不同基因型HDV基因组序列的显著差异，尤其是高变区的差异，可能至少部分是由于进化过程中多次基因重组事件导致的。基因重组可能在增加遗传多样性方面发挥重要作用。重要的是，在人及土拨鼠抗体识别的丁型肝炎病毒抗原的一个免疫原性结构域（氨基酸174 - 195）中发生了一次基因重组（核苷酸1082 - 1093）。在核苷酸1517和1535之间的另一个片段也发生了基因重组，该片段靠近一个预测的T细胞表位（氨基酸26 - 41）。在慢性感染期间不同时间点对HDV基因组的纵向分析中，这些表位发生氨基酸变化的新型优势HDV毒株通常在严重肝炎发作后出现。在肝病发作期间或发作后不久对HDV克隆的比较中，经常发现Ka/Ks比值>1，提示达尔文正向选择。因此，这两个片段的重组可能对HDV逃避免疫起重要作用。
