The broad assessment of HCV genotypes 1 and 3 antigenic targets reveals limited cross-reactivity with implications for vaccine design.
The broad assessment of HCV genotypes 1 and 3 antigenic targets reveals limited cross-reactivity with implications for vaccine design.
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对 HCV 基因型 1 和 3 抗原靶标的广泛评估揭示了有限的交叉反应性，这对疫苗设计有影响。
DOI：
10.1136/gutjnl-2014-308724
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发表时间：
2016
期刊：
影响因子：
24.5
通讯作者：
Barnes,Eleanor
中科院分区：
文献类型：
--
作者：
vonDelft,Annette;Humphreys,IslaS;Brown,Anthony;Pfafferott,Katja;Lucas,Michaela;Klenerman,Paul;Lauer,GeorgM;Cox,AndreaL;Gaudieri,Silvana;Barnes,Eleanor
开发一种在HCV基因型之间具有交叉反应性的疫苗需要关于T细胞抗原靶点的数据，这些靶点延伸到基因型1之外。我们表征了针对HCV基因型-3（在英国和亚洲最常见的感染基因型）的T细胞免疫应答，并评估了基因型内和基因型之间的交叉反应性。使用（1）重叠肽和（2）推定的人白细胞抗原（HLA）-类-I野生型和变异表位，通过预先评估与宿主HLA相关的HCV基因组多态性位点，在IFNγ-ELISpot试验中。定义了CD 4 +/CD 8 + T细胞亚群，并通过群体分析和病毒测序确定了T细胞靶点的病毒变异性。T细胞之间的交叉反应基因型-1和基因型-3的变种assessed.ResultsIn解决基因型-3感染，T细胞优先针对非结构蛋白在一个高的幅度，而在慢性疾病T细胞不存在或倾斜的目标结构蛋白。定义了对野生型而非变体HLA预测肽的额外应答。在解决感染的T细胞靶点和显性表位处，在基因型3内以及基因型1和3之间观察到主要序列病毒变异性，病毒变体之间的T细胞交叉反应性有限。共鉴定出41个CD 4/CD 8+基因型-3 T细胞靶点，与HCV基因型-1的靶点重叠最小。结论T细胞交叉反应性有限的基因型在缓解期和慢性期HCV T细胞特异性不同。因此，在自然HCV感染中靶向的病毒区域可能不作为旨在保护免受多种HCV基因型的疫苗的有吸引力的靶标。
ObjectiveDeveloping a vaccine that is cross-reactive between HCV genotypes requires data on T cell antigenic targets that extends beyond genotype-1. We characterised T cell immune responses against HCV genotype-3, the most common infecting genotype in the UK and Asia, and assessed within genotype and between genotype cross-reactivity.DesignT cell targets were identified in 140 subjects with either acute, chronic or spontaneously resolved HCV genotype-3 infection using (1) overlapping peptides and (2) putative human leucocyte antigens (HLA)-class-I wild type and variant epitopes through the prior assessment of polymorphic HCV genomic sites associated with host HLA, in IFNγ-ELISpot assays. CD4+/CD8+ T cell subsets were defined and viral variability at T cell targets was determined through population analysis and viral sequencing. T cell cross-reactivity between genotype-1 and genotype-3 variants was assessed.ResultsIn resolved genotype-3 infection, T cells preferentially targeted non-structural proteins at a high magnitude, whereas in chronic disease T cells were absent or skewed to target structural proteins. Additional responses to wild type but not variant HLA predicted peptides were defined. Major sequence viral variability was observed within genotype-3 and between genotypes 1 and 3 HCV at T cell targets in resolved infection and at dominant epitopes, with limited T cell cross-reactivity between viral variants. Overall 41 CD4/CD8+ genotype-3 T cell targets were identified with minimal overlap with those described for HCV genotype-1.ConclusionsHCV T cell specificity is distinct between genotypes with limited T cell cross-reactivity in resolved and chronic disease. Therefore, viral regions targeted in natural HCV infection may not serve as attractive targets for a vaccine that aims to protect against multiple HCV genotypes.