Cross-genotype-reactivity of the immunodominant HCVCD8 T-cell epitope NS3-1073
Cross-genotype-reactivity of the immunodominant HCVCD8 T-cell epitope NS3-1073
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DOI：
10.1016/j.vaccine.2008.05.045
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发表时间：
2008-07-23
期刊：
影响因子：
5.5
通讯作者：
Wedemeyer, H.
中科院分区：
文献类型：
--
作者：
Fytili, P.;Dalekos, G. N.;Wedemeyer, H.
hcv特异性hla - a2限制性NS3（1073）表位是丙型肝炎中最常见的表位之一。NS3（1073）特异性t细胞反应与急性hcv感染的清除相关。因此，该表位是hcv肽疫苗的一个有趣的候选表位。然而，基因型和表位突变之间的异质性必须被认为是一个障碍。通过对251名希腊和德国患者的血清进行测序，并搜索已发表的hcv基因组，与野生型基因型-1变异（CVNGVCWTV/CINGVCWTV）相比，我们鉴定出34种自然发生的NS3（1073）变异。基因型1患者的变异频率为10%。重要的是，HLA-A2结合仅在3个基因1型突变体中减少，而所有非基因I型突变体均表现出强的HLA-A2结合。通过从T细胞系中筛选28个变异，我们可以证明HCV-NS3（1073）野生型特异性T细胞表现出跨基因型反应性，特别是对基因型4-6变异。然而，即使在基因型1中保守的aa交换，tcr结合域内的单个aa变化也完全取消了识别。来自康复、慢性感染和hcv阴性个体的NS3（1073）特异性t细胞系在交叉识别模式上没有显着差异，尽管NS3（1073）特异性t细胞的增殖在两组之间存在显着差异。重要的是，在急性HCV感染患者和接种含有NS3(1073)-野生型肽的肽疫苗IC41的健康志愿者体内，对28种变体的识别模式也是相同的。因此，HCV NS3（1073）特异性CD8 T细胞的部分跨基因型识别是可能的；然而，即使是单一的aa交换也会显著限制含有NS3(1073)-野生型肽的疫苗的潜在效力。(C) 2008 Elsevier Ltd版权所有。
The HCV-specific HLA-A2-restricted NS3(1073) epitope is one of the most frequently recognized epitopes in hepatitis C. NS3(1073)-specific T-cell responses are associated with clearance of acute HCV-infection. Therefore this epitope is an interesting candidate for a HCV-peptide vaccine. However, heterogeneity between genotypes and mutations in the epitope has to be considered as an obstacle.We here identified 34 naturally occurring NS3(1073)-variants, as compared with the wild type genotype-1 variants (CVNGVCWTV/CINGVCWTV) by sequencing sera of 251 Greek and German patients and searching for published HCV-genomes. The frequency of variants among genotype-1 patients was 10%. Importantly, HLA-A2 binding was reduced only in 3 genotype 1 mutants while all non-genotype I variants showed strong HLA-A2-binding. By screening 28 variants in ELISPOT assays from T cell lines we could demonstrate that HCV-NS3(1073)-wild-type-specific T-cells displayed cross-genotype-reactivity, in particular against genotypes 4-6 variants. However, single aa changes within the TCR-binding domain completely abolished recognition even in case of conservative aa exchanges within genotype-1. NS3(1073)-specific T-cell lines from recovered, chronically infected, and HCV-negative individuals showed no major difference in the pattern of cross-recognition although the proliferation of NS3(1073)-specific T-cells differed significantly between the groups. Importantly, the recognition pattern against the 28 variants was also identical directly ex vivo in a patient with acute HCV infection and a healthy volunteer vaccinated with the peptide vaccine IC41 containing the NS3(1073)-wild-type peptide.Thus, partial cross-genotype recognition of HCV NS3(1073)-specific CD8 T cells is possible; however, even single aa exchanges can significantly limit the potential efficacy of vaccines containing the NS3(1073)-wildtype peptide. (C) 2008 Elsevier Ltd. All rights reserved.