Harcourt G C, Lucas M, Sheridan I, Barnes E, Phillips R, Klenerman P
Nuffield Department of Clinical Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK.
J Viral Hepat. 2004 Jul;11(4):324-31. doi: 10.1111/j.1365-2893.2004.00516.x.
Cellular immunity plays an important role in the control of persistent virus infections such as hepatitis C virus (HCV). Antiviral CD4(+) T cell responses have been shown to accompany resolution of acute disease and there is also a consistent association between HLA Class II genes, notably HLADRB11101 (and the closely linked HLADQB10301) and disease resolution. We initially mapped longitudinal CD4(+) T cell responses in an individual after spontaneous resolution of acute HCV, and identified three HLA-DR11-restricted responses which vary in immunodominance over time. Functional assays and HLA Class II tetramer staining revealed one to be a response to a commonly recognized epitope, NS3(1248-1261), although cytokine capture assays showed these specific cells to be at a very low frequency. In this patient, and in others reported, this most frequently recognized HLA-DR11 restricted epitope is not immunodominant. We analysed whether sequence variability within and between genotypes might account for differences in recognition of HLA-DR11 restricted epitopes. We found that a limited number, including NS3(1248-1261), showed extreme sequence conservation. Within NS3, the ability of peptides to accept amino acid substitutions was clearly related to the structure of the protein. Overall the data provide a deeper understanding of the relationship between protein structure and variability of HLA-DR11 restricted peptides and may explain the apparent dominance of responses to NS3(1248-1261) across studies but not within an individual immune response.
细胞免疫在控制持续性病毒感染（如丙型肝炎病毒，HCV）中发挥着重要作用。抗病毒CD4(+) T细胞反应已被证明与急性疾病的缓解相伴，并且HLA II类基因，特别是HLADRB11101（以及紧密连锁的HLADQB10301）与疾病缓解之间也存在一致的关联。我们最初绘制了一名急性HCV自发缓解个体的纵向CD4(+) T细胞反应图谱，并确定了三种受HLA-DR11限制的反应，它们在免疫优势方面随时间变化。功能测定和HLA II类四聚体染色显示其中一种是对常见识别表位NS3(1248 - 1261)的反应，尽管细胞因子捕获测定显示这些特定细胞的频率非常低。在该患者以及其他报道的患者中，这种最常被识别的受HLA-DR11限制的表位并非免疫优势表位。我们分析了基因型内和基因型间的序列变异性是否可能解释对受HLA-DR11限制表位识别的差异。我们发现包括NS3(1248 - 1261)在内的少数表位显示出极端的序列保守性。在NS3内，肽接受氨基酸替代的能力显然与蛋白质结构有关。总体而言，这些数据提供了对蛋白质结构与受HLA-DR11限制肽的变异性之间关系的更深入理解，并可能解释了在各项研究中对NS3(1248 - 1261)反应的明显优势，但在个体免疫反应中并非如此。
