Constraints on Viral Evolution during Chronic Hepatitis C Virus Infection Arising from a Common-Source Exposure
Constraints on Viral Evolution during Chronic Hepatitis C Virus Infection Arising from a Common-Source Exposure
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DOI：
10.1128/jvi.01440-12
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发表时间：
2012-12-01
影响因子：
5.4
通讯作者：
Ray, Stuart C.
中科院分区：
文献类型：
--
作者：
Bailey, Justin R.;Laskey, Sarah;Ray, Stuart C.
非凡的病毒序列多样性和快速的病毒遗传进化是丙型肝炎病毒（HCV）感染的标志。病毒序列进化先前已显示在急性HCV感染中介导逃避细胞毒性T淋巴细胞（CTL）和中和抗体应答。HCV在慢性感染期间继续演变，但驱动这些变化的压力定义不清。我们分析了血浆病毒序列演变的5.2 kb半基因组从多个纵向时间点分离的个人在爱尔兰抗D队列，谁是感染HCV从一个共同的来源在1977年至1978年。我们发现，在慢性感染后期分离的不同血浆时间点，在遗传学上不同的准种群体，这表明随着时间的推移，正在进行的病毒进化和准种替换。我们看到了早期压力驱动净进化远离计算重建的共同祖先的证据，称为Bole1b，在预测的CTL表位和E1E2中，在基因组的其余部分中朝着和远离Bole1b氨基酸序列的平衡进化。在慢性感染后期，向Bole1b序列进化的速率增加，导致整个5.2 kb半基因组相对于Bole1b的净中性进化。令人惊讶的是，即使在慢性感染后期，仍然可以观察到远离感染接种物序列的净氨基酸进化。这些数据表明，在慢性感染后期，持续的HCV进化不是随机的遗传漂变，而是朝向共同祖先的强大压力和远离接种物病毒序列的同时净持续进化的产物，可能平衡复制适应性和持续的免疫逃逸。
Extraordinary viral sequence diversity and rapid viral genetic evolution are hallmarks of hepatitis C virus (HCV) infection. Viral sequence evolution has previously been shown to mediate escape from cytotoxic T-lymphocyte (CTL) and neutralizing antibody responses in acute HCV infection. HCV evolution continues during chronic infection, but the pressures driving these changes are poorly defined. We analyzed plasma virus sequence evolution in 5.2-kb hemigenomes from multiple longitudinal time points isolated from individuals in the Irish anti-D cohort, who were infected with HCV from a common source in 1977 to 1978. We found phylogenetically distinct quasispecies populations at different plasma time points isolated late in chronic infection, suggesting ongoing viral evolution and quasispecies replacement over time. We saw evidence of early pressure driving net evolution away from a computationally reconstructed common ancestor, known as Bole1b, in predicted CTL epitopes and E1E2, with balanced evolution toward and away from the Bole1b amino acid sequence in the remainder of the genome. Late in chronic infection, the rate of evolution toward the Bole1b sequence increased, resulting in net neutral evolution relative to Bole1b across the entire 5.2-kb hemigenome. Surprisingly, even late in chronic infection, net amino acid evolution away from the infecting inoculum sequence still could be observed. These data suggest that, late in chronic infection, ongoing HCV evolution is not random genetic drift but rather the product of strong pressure toward a common ancestor and concurrent net ongoing evolution away from the inoculum virus sequence, likely balancing replicative fitness and ongoing immune escape.