Immunological significance of cytotoxic T lymphocyte epitope variants in patients chronically infected by the hepatitis C virus
Immunological significance of cytotoxic T lymphocyte epitope variants in patients chronically infected by the hepatitis C virus
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DOI：
10.1172/jci119778
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发表时间：
1997-11-01
影响因子：
15.9
通讯作者：
Chisari, FV
中科院分区：
文献类型：
--
作者：
Chang, KM;Rehermann, B;Chisari, FV
本研究旨在验证丙型肝炎病毒（HCV）逃逸变异的细胞毒性T淋巴细胞（CTL）选择在丙型肝炎病毒（HCV）持久性中起作用的假设。慢性丙型肝炎患者外周血CTL对10个原型HCV肽（la基因型）的反应性与每个患者感染病毒编码的相应序列进行了比较。变异病毒肽序列在存在CTL反应时的频率是不存在CTL反应时的三倍，而CTL反应在变异病毒肽序列中检测到的频率是原型病毒肽序列检测到的两倍。此外，超过一半的患者感染了潜在的CTL逃逸变异，这些变异含有非免疫原性和非交叉反应性变异肽，其中许多变异肽显示出hla结合亲和力降低。令人惊讶的是，长达46个月的随访分析显示，与最初观察到的相对较高的逃逸变异频率相反，随后CTL逃逸变异的出现率非常低。有趣的是，检测到的一个逃逸变体被证明是CTL拮抗剂。总的来说，这些观察结果表明，表位变异的CTL选择可能在这些患者进入研究之前就已经发生了，并且它可能在HCV持续存在中发挥作用。然而，慢性感染患者持续CTL选择的低明显率表明，如果在HCV感染期间发生CTL逃逸，这可能是一个早期事件。
This study was performed to test the hypothesis that cytotoxic T lymphocyte (CTL) selection of hepatitis C virus (HCV) escape variants plays a role in HCV persistence. The peripheral blood CTL responsiveness of patients with well-established chronic hepatitis C to a panel of 10 prototype HCV peptides (genotype la) was compared with the corresponding sequences encoded by the infecting viruses in each patient. Variant viral peptide sequences were threefold more frequent in the presence of a CTL response than in its absence, and CTL responses were detected nearly twice as often in association with variant rather than with prototype viral peptide sequences. Furthermore, over half of the patients were infected with potential CTL escape variants that contained nonimmunogenic and noncross-reactive variant peptides many of which displayed reduced HLA-binding affinity, Surprisingly, follow up analysis over a period of up to 46 mo revealed that, in contrast to the relatively high frequency of escape variants initially observed, the subsequent emergence rate of CTL escape variants was very low. Interestingly, the one escape variant that was detected proved to be a CTL antagonist. Collectively, these observations suggest that CTL selection of epitope variants may have occurred in these patients before their entrance into the study and that it may have played a role in HCV persistence, The low apparent rate of ongoing CTL selection in chronically infected patients, however, suggests that if CTL escape occurs during HCV infection it is probably an early event.