Kuntzen Thomas, Timm Joerg, Berical Andrew, Lewis-Ximenez Lia L, Jones Andrea, Nolan Brian, Schulze zur Wiesch Julian, Li Bin, Schneidewind Arne, Kim Arthur Y, Chung Raymond T, Lauer Georg M, Allen Todd M
Massachusetts General Hospital, Infectious Disease, 13th Street, Charlestown, MA 02129, USA.
J Virol. 2007 Nov;81(21):11658-68. doi: 10.1128/JVI.00995-07. Epub 2007 Aug 15.
CD8(+)-T-cell responses play an important role in the containment and clearance of hepatitis C virus (HCV) infection, and an association between viral persistence and development of viral escape mutations has been postulated. While escape from CD8+ -T-cell responses has been identified as a major driving force for the evolution of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV), a broader characterization of this relationship is needed in HCV infection. To determine the extent, kinetics, and driving forces of HCV sequence evolution, we sequenced the entire HCV genome longitudinally in four subjects monitored for up to 30 months after acute infection. For two subjects the transmission sources were also available. Of 53 total non-envelope amino acid substitutions detected, a majority represented forward mutations away from the consensus sequence. In contrast to studies in HIV and SIV, however, only 11% of these were associated with detectable CD8+ T-cell responses. Interestingly, 19% of non-envelope mutations represented changes toward the consensus sequence, suggesting reversion in the absence of immune pressure upon transmission. Notably, the rate of evolution of forward and reverse mutations correlated with the conservation of each residue, which is indicative of structural constraints influencing the kinetics of viral evolution. Finally, the rate of sequence evolution was observed to decline over the course of infection, possibly reflective of diminishing selection pressure by dysfunctional CD8+ T cells. Taken together, these data provide insight into the extent to which HCV is capable of evading early CD8+ T-cell responses and support the hypothesis that dysfunction of CD8+ T cells may be associated with failure to resolve HCV infections.
CD8(+) T细胞反应在丙型肝炎病毒（HCV）感染的控制和清除中发挥着重要作用，并且病毒持续存在与病毒逃逸突变的发生之间的关联已被提出。虽然从CD8+ T细胞反应中逃逸已被确定为人类免疫缺陷病毒（HIV）和猴免疫缺陷病毒（SIV）进化的主要驱动力，但在HCV感染中需要对这种关系进行更广泛的表征。为了确定HCV序列进化的程度、动力学和驱动力，我们在急性感染后长达30个月进行监测的4名受试者中纵向测序了整个HCV基因组。对于两名受试者，还可获得传播源。在总共检测到的53个非包膜氨基酸替代中，大多数代表远离共有序列的正向突变。然而，与HIV和SIV的研究不同，这些替代中只有11%与可检测到的CD8+ T细胞反应相关。有趣的是，19%的非包膜突变代表向共有序列的变化，表明在传播时缺乏免疫压力的情况下发生了回复突变。值得注意的是，正向和反向突变的进化速率与每个残基的保守性相关，这表明结构限制影响了病毒进化的动力学。最后，观察到序列进化速率在感染过程中下降，这可能反映了功能失调的CD8+ T细胞的选择压力减小。综上所述，这些数据提供了关于HCV能够逃避早期CD8+ T细胞反应程度的见解，并支持CD8+ T细胞功能失调可能与无法清除HCV感染相关的假设。
