Identification of antigenic escape variants in an immunodominant epitope of hepatitis C virus
Identification of antigenic escape variants in an immunodominant epitope of hepatitis C virus
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DOI：
10.1093/intimm/11.4.577
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发表时间：
1999-04-01
影响因子：
4.4
通讯作者：
Wang, HR
中科院分区：
文献类型：
--
作者：
Eckels, DD;Zhou, H;Wang, HR
许多研究人员推测，丙型肝炎病毒(HCV)逃避免疫系统的一个机制是通过形成逃逸突变。这一假说在很大程度上是基于观察到的病毒基因组的变异性，导致在感染过程中进化出不同的准种。这种多样化是病毒RNA聚合酶不忠、免疫驱动的选择或这两个过程的组合的产物，这一点尚未得到解决。我们已经检测了编码病毒解旋酶已知免疫优势区域的丙型肝炎病毒RNA的一个特定片段的序列变异性，即非结构蛋白3的358-375个氨基酸。利用序列特异性寡核苷酸探针杂交和DNA自动测序，我们报告了高频率的突变，基本上所有这些突变都导致了氨基酸替换，为了评估这些突变的生物学影响，我们在T细胞增殖试验中将相应的化学合成肽与野生型肽进行了比较。我们观察到，相当大一部分这样的多肽刺激来自慢性感染患者的外周T细胞的增殖减弱或可以忽略不计。这一观察结果与免疫介导的在表位水平上选择逃逸变异体的预期一致。我们推测，这种机制在丙型肝炎病毒感染的免疫发病机制中可能很重要。
Numerous investigators have postulated that one mechanism by which hepatitis C virus (HCV) may evade the immune system is through the formation of escape mutants. This hypothesis is based largely on the observed mutability of the viral genome resulting in evolution of diverse quasispecies over the course of infection. That such diversification is a product of viral RNA polymerase infidelity, immune-driven selection or a combination of the two processes has not been addressed. We have examined sequence variability in a specific segment of HCV RNA encoding a known immunodominant region of the viral helicase, amino acids 358-375 of the non-structural 3 protein. Using sequence-specific oligonucleotide probe hybridization and automated DNA sequencing, we report a high frequency of mutations, essentially all of which result in amino acid replacements, To assess the biological impact of such mutations, corresponding chemically synthesized peptides were compared to wild-type peptide in T cell proliferation assays. We observed that a sizeable fraction of such peptides stimulated attenuated or negligible levels of proliferation by peripheral T cells from a chronically infected patient. This observation is consistent with expectations for immune-mediated selection of escape variants at the epitope level. We postulate that such a mechanism may be important in the immunopathogenesis of HCV infections.