Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Research II Building, Room WA4104, 700 Children's Drive, Columbus, OH 43205, USA.
J Virol. 2011 Nov;85(22):11833-45. doi: 10.1128/JVI.02654-10. Epub 2011 Sep 7.
The RNA genome of the hepatitis C virus (HCV) diversifies rapidly during the acute phase of infection, but the selective forces that drive this process remain poorly defined. Here we examined whether Darwinian selection pressure imposed by CD8(+) T cells is a dominant force driving early amino acid replacement in HCV viral populations. This question was addressed in two chimpanzees followed for 8 to 10 years after infection with a well-defined inoculum composed of a clonal genotype 1a (isolate H77C) HCV genome. Detailed characterization of CD8(+) T cell responses combined with sequencing of recovered virus at frequent intervals revealed that most acute-phase nonsynonymous mutations were clustered in class I epitopes and appeared much earlier than those in the remainder of the HCV genome. Moreover, the ratio of nonsynonymous to synonymous mutations, a measure of positive selection pressure, was increased 50-fold in class I epitopes compared with the rest of the HCV genome. Finally, some mutation of the clonal H77C genome toward a genotype 1a consensus sequence considered most fit for replication was observed during the acute phase of infection, but the majority of these amino acid substitutions occurred slowly over several years of chronic infection. Together these observations indicate that during acute hepatitis C, virus evolution was driven primarily by positive selection pressure exerted by CD8(+) T cells. This influence of immune pressure on viral evolution appears to subside as chronic infection is established and genetic drift becomes the dominant evolutionary force.
丙型肝炎病毒（HCV）的 RNA 基因组在感染的急性期迅速多样化，但驱动这一过程的选择压力仍未得到明确界定。在这里，我们研究了 CD8(+) T 细胞施加的达尔文选择压力是否是驱动 HCV 病毒群体早期氨基酸替换的主要力量。这个问题在两只感染了由明确接种物组成的 1a 型（分离株 H77C）HCV 基因组的黑猩猩中进行了 8 到 10 年的随访。详细的 CD8(+) T 细胞反应特征结合频繁间隔回收病毒的测序显示，大多数急性期非同义突变聚集在 I 类表位中，并且比 HCV 基因组的其余部分更早出现。此外，非同义突变与同义突变的比值（衡量正选择压力的指标）在 I 类表位中比 HCV 基因组的其余部分增加了 50 倍。最后，在感染的急性期观察到克隆 H77C 基因组向最适合复制的 1a 型共识序列的一些突变，但这些氨基酸取代中的大多数在慢性感染的几年中缓慢发生。这些观察结果表明，在急性丙型肝炎期间，病毒进化主要是由 CD8(+) T 细胞施加的正选择压力驱动的。随着慢性感染的建立和遗传漂变成为主要的进化力量，免疫压力对病毒进化的这种影响似乎会减弱。
