High resolution analysis of cellular immune responses in resolved and persistent hepatitis C virus infection
High resolution analysis of cellular immune responses in resolved and persistent hepatitis C virus infection
复制标题
DOI：
10.1053/j.gastro.2004.06.015
复制
发表时间：
2004-09-01
期刊：
影响因子：
29.4
通讯作者：
Klenerman, P
中科院分区：
文献类型：
--
作者：
Lauer, GM;Barnes, E;Klenerman, P
背景与目的：细胞免疫反应被认为在丙型肝炎病毒感染的解决中起着关键作用。虽然一直以来的研究表明，在自然消退的患者中，CD4+T细胞反应保持不变，而在持续感染的患者中，CD4+T细胞反应消失，但CD8+T细胞反应的作用仍然存在争议。以前的研究主要集中在有限的HLA等位基因和预定义的CD8+T细胞表位，因此，全面的研究仍有待进行。方法：为了了解与自发解体相关的免疫反应的组成，我们使用跨越整个基因组的丙型肝炎病毒多肽，对20名具有不同人类白细胞抗原的丙型肝炎病毒感染者的CD8+T细胞反应进行了全面定位。我们用ELISpot、I类四聚体、细胞内细胞因子染色和细胞溶解试验分析了大小、广度、功能和表型。我们同时研究了持续感染中的丙型肝炎病毒特异性反应和病毒序列变异。结果：感染已解决的个体的反应强烈而广泛，对抗原有强烈的增殖反应。在那些持续感染的人中，很少在体外检测到反应，当存在时，反应是狭隘的和微弱的。然而，它们也在体外增殖。尽管两个队列中的个体之间经常有相同的HLA等位基因，但主要的靶表位有所不同。结论：这些数据表明，在大多数已痊愈的丙型肝炎病毒感染者中，观察到持续的、强烈的CD8+T细胞反应，这为加强CD8+T细胞反应以预防或治疗丙型肝炎病毒感染的策略提供了支持，但也突显了可能需要激发的反应的多样性，以提供保护。
Background & Aims: Cellular immune responses are thought to play a key role in the resolution of primary HCV infection. Although it has been consistently shown that CD4+ T-cell responses are maintained in those with spontaneous resolution but lost in those with persistent infection, the role of CD8+ T-cell responses remains controversial. Previous studies have largely focused on limited HLA alleles and predefined CD8+ T-cell epitopes, and, thus, comprehensive studies remain to be performed. Methods: To understand the composition of the immune response associated with spontaneous resolution, we comprehensively mapped CD8+ T-cell responses in 20 HLA-diverse persons with resolved HCV infection, using HCV peptides spanning the entire genome. We analyzed the magnitude, breadth, function, and phenotype using ELISpot, class-I tetramers, intracellular cytokine staining, and cytolytic assays. We studied in parallel HCV-specific responses and viral sequence variation in persistent infection. Results: Responses in individuals with resolved infection were strong and broad with robust proliferation in response to antigen. Responses in those persistently infected were rarely detected ex vivo and, when present, were narrowly directed and weak. However, they also proliferated in vitro. Dominant target epitopes differed among individuals in both cohorts, despite frequently shared HLA-alleles. Conclusions: These data indicate that persisting, strong CD8+ T-cell responses are observed in the majority of persons with resolved HCV infection and provide support for strategies to boost CD8+ T-cell responses for the prevention or treatment of HCV infection but also highlight the diversity of responses that may need to be elicited to provide protection.