CYTOTOXIC T-LYMPHOCYTE RESPONSE TO HEPATITIS-C VIRUS-DERIVED PEPTIDES CONTAINING THE HLA A2.1 BINDING MOTIF
CYTOTOXIC T-LYMPHOCYTE RESPONSE TO HEPATITIS-C VIRUS-DERIVED PEPTIDES CONTAINING THE HLA A2.1 BINDING MOTIF
复制标题
DOI：
10.1172/jci117694
复制
发表时间：
1995-02-01
影响因子：
15.9
通讯作者：
CHISARI, FV
中科院分区：
文献类型：
--
作者：
CERNY, A;MCHUTCHISON, JG;CHISARI, FV
HLA I类限制性细胞毒性T淋巴细胞（CTL）反应是病毒感染的主要防御机制。研究表明，在丙型肝炎病毒（HCV）感染过程中，CTL应答可能参与病毒清除和肝细胞损伤。为了验证这一假设，需要了解HCV特异性细胞毒性效应细胞的特征，并鉴定它们应答的靶抗原。为了开始这一过程，我们用一组含有HLA-A2结合基序的130种HCV衍生肽刺激来自一组HLA-A2阳性慢性丙型肝炎患者的外周血单核细胞（PBMC）。测试效应细胞裂解HLA-A2匹配的靶细胞的能力，所述靶细胞用肽致敏或用含有HCV序列的牛痘病毒构建体感染。使用这种方法，我们已经确定了九个免疫原性肽在HCV，其中三个是来自推定的核心蛋白，三个从非结构（NS）3域，两个从NS 4和一个从NS 5。选定的反应显示为HLA-A2限制性的，由CD 8（+）T细胞介导，并识别内源性合成的病毒抗原。出乎意料的是，肽特异性CTL应答也可以在血清阴性个体中诱导，表明幼稚CTL前体的体外活化。与未感染的对照组相比，感染患者中肽特异性CTL的前体频率高10至100倍，并且通过去除CD 45 RO（+）（记忆）T细胞，应答大大减弱。明确需要进一步的定量研究来确定HCV特异性CTL应答和这种疾病的临床过程之间是否存在相关性。人CTL应答HCV的分子靶点的定义创造了这种机会，也可能有助于开发基于T细胞的HCV疫苗。
The HLA class I-restricted cytotoxic T lymphocyte (CTL) response is a major defense mechanism in viral infections. It has been suggested that the CTL response may contribute to viral clearance and liver cell injury during hepatitis C virus (HCV) infection. To test this hypothesis requires an understanding of the characteristics of HCV-specific cytotoxic effector cells and identification of the target antigens to which they respond. To begin this process we stimulated peripheral blood mononuclear cells (PBMC) from a group of HLA-A2 positive patients with chronic hepatitis C with a panel of 130 HCV-derived peptides containing the HLA-A2 binding motif. Effector cells were tested for their capacity to lyse HLA-A2-matched target cells that were either sensitized with peptide or infected with a vaccinia virus construct containing HCV sequences. Using this approach we have identified nine immunogenic peptides in HCV, three of which are derived from the putative core protein, three from the nonstructural (NS) 3 domain, two from NS4 and one from NS5. Selected responses were shown to be HLA-A2 restricted, mediated by CD8(+) T cells and to recognize endogenously synthesized viral antigen. Unexpectedly, peptide-specific CTL responses could also be induced in seronegative individuals, suggesting in vitro activation of naive CTL precursors. The precursor frequency of peptide-specific CTL was 10 to 100-fold higher in infected patients compared to uninfected controls, and the responses were greatly diminished by removal of CD45 RO(+) (memory)T cells. Further quantitative studies are clearly required to establish whether a correlation exists between the HCV-specific CTL response and the clinical course of this disease. Definition of the molecular targets of the human CTL response to HCV creates this opportunity, and may also contribute to the development of a T cell-based HCV vaccine.