Higashi Y, Kakumu S, Yoshioka K, Wakita T, Mizokami M, Ohba K, Ito Y, Ishikawa T, Takayanagi M, Nagai Y
Third Department of Internal Medicine, Nagoya University School of Medicine, Japan.
Virology. 1993 Dec;197(2):659-68. doi: 10.1006/viro.1993.1641.
To substantiate and extend the quasispecies model of hepatitis C virus (HCV), we made a pairwise comparison in the nucleotide and deduced amino acid sequences for multiple recombinant clones of the E2/NS1 region, which derived from each blood sample taken from five patients of subtype II or subtype III infection at different stages. Sequence heterogeneity among the clones was generally high. The heterogeneity, however, changed temporally and appeared to be significantly lowered after interferon therapy. The temporal fluctuation involved selection of particular amino acids at particular positions, which had represented only a minor fraction or had been absent in the previous clones. Evolution of defective viruses was featured by most of the cases, the proportion of which also fluctuated temporally and was extremely high at a certain stage in one of the patients. A comparison was also made among the clones from different stages of each patient and revealed highly divergent clones. An extreme case of subtype III infection showed sequence differences well beyond those among chronologically and geographically different isolates of subtype I or subtype II, which were defined by the same calculation of available sequence data. These features of HCV genome suggest that the virus could circulate as an extremely heterogeneous population including defective viruses and that this heterogeneity lends itself to selection pressures including interferon therapy and host immune response. Our results also indicate an absolute need of population based approach in HCV genetics.
为了证实并扩展丙型肝炎病毒（HCV）的准种模型，我们对E2/NS1区域的多个重组克隆的核苷酸和推导的氨基酸序列进行了两两比较，这些克隆来自五名处于不同阶段的II型或III型感染患者的每份血样。克隆之间的序列异质性通常较高。然而，这种异质性随时间变化，并且在干扰素治疗后似乎显著降低。时间波动涉及特定位置特定氨基酸的选择，这些氨基酸在先前的克隆中仅占一小部分或不存在。大多数情况下存在缺陷病毒的进化，其比例也随时间波动，在一名患者的某个阶段极高。我们还对每位患者不同阶段的克隆进行了比较，发现克隆高度不同。一个III型感染的极端案例显示，其序列差异远远超过通过相同计算可用序列数据所定义的I型或II型在时间和地理上不同的分离株之间的差异。HCV基因组的这些特征表明，该病毒可能作为包括缺陷病毒在内的极其异质的群体循环，并且这种异质性使其易于受到包括干扰素治疗和宿主免疫反应在内的选择压力。我们的结果还表明，在HCV遗传学中绝对需要基于群体的方法。
