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Comparative vaccine studies in HLA-A2.1-transgenic mice reveal a clustered organization of epitopes presented in hepatitis C virus natural infection.在 HLA - A2.1转基因小鼠中进行的比较疫苗研究揭示了丙型肝炎病毒自然感染中呈现的表位的聚集组织。
J Virol. 2002 Dec;76(24):12735-46. doi: 10.1128/jvi.76.24.12735-12746.2002.
2
DNA immunization with hepatitis C virus (HCV) polycistronic genes or immunization by HCV DNA priming-recombinant canarypox virus boosting induces immune responses and protection from recombinant HCV-vaccinia virus infection in HLA-A2.1-transgenic mice.用丙型肝炎病毒（HCV）多顺反子基因进行DNA免疫或通过HCV DNA初免-重组金丝雀痘病毒加强免疫可诱导HLA-A2.1转基因小鼠产生免疫反应，并使其免受重组HCV-痘苗病毒感染。
J Virol. 2003 Jan;77(1):382-90. doi: 10.1128/jvi.77.1.382-390.2003.
3
Genetic immunization and comprehensive screening approaches in HLA-A2 transgenic mice lead to the identification of three novel epitopes in hepatitis C virus NS3 antigen.在HLA - A2转基因小鼠中采用基因免疫和综合筛选方法，鉴定出丙型肝炎病毒NS3抗原中的三个新表位。
J Med Virol. 2004 Nov;74(3):397-405. doi: 10.1002/jmv.20189.
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In vivo hierarchy of immunodominant and subdominant HLA-A*0201-restricted T-cell epitopes of HBx antigen of hepatitis B virus.乙型肝炎病毒X蛋白抗原中免疫显性和亚显性HLA-A*0201限制性T细胞表位的体内层级关系
Microbes Infect. 2005 Apr;7(4):626-34. doi: 10.1016/j.micinf.2004.12.022. Epub 2005 Mar 16.
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Oral immunization with HCV-NS3-transformed Salmonella: induction of HCV-specific CTL in a transgenic mouse model.用丙型肝炎病毒非结构蛋白3（HCV-NS3）转化的沙门氏菌进行口服免疫：在转基因小鼠模型中诱导HCV特异性细胞毒性T淋巴细胞（CTL）
Gastroenterology. 2001 Nov;121(5):1158-66. doi: 10.1053/gast.2001.29311.
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Adjuvant activities of novel cytokines, interleukin-23 (IL-23) and IL-27, for induction of hepatitis C virus-specific cytotoxic T lymphocytes in HLA-A*0201 transgenic mice.新型细胞因子白细胞介素-23（IL-23）和IL-27在HLA-A*0201转基因小鼠中对诱导丙型肝炎病毒特异性细胞毒性T淋巴细胞的佐剂活性。
J Virol. 2004 Sep;78(17):9093-104. doi: 10.1128/JVI.78.17.9093-9104.2004.
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Dendritic cell-mediated, DNA-based vaccination against hepatitis C induces the multi-epitope-specific response of humanized, HLA transgenic mice.基于DNA的树突状细胞介导的丙型肝炎疫苗接种可诱导人源化、HLA转基因小鼠的多表位特异性应答。
PLoS One. 2014 Aug 11;9(8):e104606. doi: 10.1371/journal.pone.0104606. eCollection 2014.
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Identification of A2-restricted hepatitis C virus-specific cytotoxic T lymphocyte epitopes from conserved regions of the viral genome.从病毒基因组保守区域鉴定A2限制型丙型肝炎病毒特异性细胞毒性T淋巴细胞表位
Int Immunol. 1996 May;8(5):651-9. doi: 10.1093/intimm/8.5.651.
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Immunogenic variation between multiple HLA-A*0201-restricted, Hepatitis C Virus-derived epitopes for cytotoxic T lymphocytes.多种HLA-A*0201限制性丙型肝炎病毒来源的细胞毒性T淋巴细胞表位之间的免疫原性差异
Viral Immunol. 2006 Summer;19(3):458-67. doi: 10.1089/vim.2006.19.458.
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Different hepatitis C virus nonstructural protein 3 (Ns3)-DNA-expressing vaccines induce in HLA-A2.1 transgenic mice stable cytotoxic T lymphocytes that target one major epitope.不同的丙型肝炎病毒非结构蛋白3（Ns3）表达DNA疫苗可在HLA - A2.1转基因小鼠中诱导出针对一个主要表位的稳定细胞毒性T淋巴细胞。
Hepatology. 2001 Dec;34(6):1206-17. doi: 10.1053/jhep.2001.29304.

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T- and B-cell responses to multivalent prime-boost DNA and viral vectored vaccine combinations against hepatitis C virus in non-human primates.非人灵长类动物中针对丙型肝炎病毒的多价初免-加强DNA和病毒载体疫苗组合的T细胞和B细胞反应。
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Hum Vaccin Immunother. 2016 Mar 3;12(3):829-36. doi: 10.1080/21645515.2015.1103405.
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Identification and retrospective validation of T-cell epitopes in the hepatitis C virus genotype 4 proteome: an accelerated approach toward epitope-driven vaccine development.鉴定和回顾性验证丙型肝炎病毒 4 型蛋白组中的 T 细胞表位：一种加速表位驱动疫苗开发的方法。
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本文引用的文献

1
Tumor necrosis factor genetic polymorphisms and response to antiviral therapy in patients with chronic hepatitis C.肿瘤坏死因子基因多态性与慢性丙型肝炎患者抗病毒治疗反应
Am J Gastroenterol. 2002 Mar;97(3):714-20. doi: 10.1111/j.1572-0241.2002.05552.x.
2
Recombinant canarypox vaccine-elicited CTL specific for dominant and subdominant simian immunodeficiency virus epitopes in rhesus monkeys.重组金丝雀痘病毒疫苗在恒河猴体内引发针对猿猴免疫缺陷病毒显性和隐性表位的细胞毒性T淋巴细胞。
J Immunol. 2002 Feb 15;168(4):1847-53. doi: 10.4049/jimmunol.168.4.1847.
3
Hepatitis C virus non-structural protein 3-specific cellular immune responses following single or combined immunization with DNA or recombinant Semliki Forest virus particles.用DNA或重组塞姆利基森林病毒颗粒进行单次或联合免疫后丙型肝炎病毒非结构蛋白3特异性细胞免疫反应
J Gen Virol. 2002 Feb;83(Pt 2):369-381. doi: 10.1099/0022-1317-83-2-369.
4
Replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity.无复制能力的腺病毒疫苗载体可引发有效的抗免疫缺陷病毒免疫力。
Nature. 2002 Jan 17;415(6869):331-5. doi: 10.1038/415331a.
5
The outcome of hepatitis C virus infection is predicted by escape mutations in epitopes targeted by cytotoxic T lymphocytes.细胞毒性T淋巴细胞靶向表位中的逃逸突变可预测丙型肝炎病毒感染的结果。
Immunity. 2001 Dec;15(6):883-95. doi: 10.1016/s1074-7613(01)00245-x.
6
Effect of interferon-alpha therapy on epitope-specific cytotoxic T lymphocyte responses in hepatitis C virus-infected individuals.α干扰素治疗对丙型肝炎病毒感染个体中表位特异性细胞毒性T淋巴细胞反应的影响。
Eur J Immunol. 2002 Jan;32(1):144-54. doi: 10.1002/1521-4141(200201)32:1<144::AID-IMMU144>3.0.CO;2-X.
7
Potentiation of simian immunodeficiency virus (SIV)-specific CD4(+) and CD8(+) T cell responses by a DNA-SIV and NYVAC-SIV prime/boost regimen.DNA-SIV与NYVAC-SIV初免/加强免疫方案增强猿猴免疫缺陷病毒（SIV）特异性CD4(+)和CD8(+) T细胞反应
J Immunol. 2001 Dec 15;167(12):7180-91. doi: 10.4049/jimmunol.167.12.7180.
8
Different hepatitis C virus nonstructural protein 3 (Ns3)-DNA-expressing vaccines induce in HLA-A2.1 transgenic mice stable cytotoxic T lymphocytes that target one major epitope.不同的丙型肝炎病毒非结构蛋白3（Ns3）表达DNA疫苗可在HLA - A2.1转基因小鼠中诱导出针对一个主要表位的稳定细胞毒性T淋巴细胞。
Hepatology. 2001 Dec;34(6):1206-17. doi: 10.1053/jhep.2001.29304.
9
Determinants of viral clearance and persistence during acute hepatitis C virus infection.急性丙型肝炎病毒感染期间病毒清除和持续存在的决定因素。
J Exp Med. 2001 Nov 19;194(10):1395-406. doi: 10.1084/jem.194.10.1395.
10
Induction of hepatitis C virus E1 envelope protein-specific immune response can be enhanced by mutation of N-glycosylation sites.丙型肝炎病毒E1包膜蛋白特异性免疫反应的诱导可通过N-糖基化位点的突变得到增强。
J Virol. 2001 Dec;75(24):12088-97. doi: 10.1128/JVI.75.24.12088-12097.2001.

在 HLA - A2.1转基因小鼠中进行的比较疫苗研究揭示了丙型肝炎病毒自然感染中呈现的表位的聚集组织。

Comparative vaccine studies in HLA-A2.1-transgenic mice reveal a clustered organization of epitopes presented in hepatitis C virus natural infection.

作者信息

Himoudi Nourredine, Abraham Jean-Daniel, Fournillier Anne, Lone Yu Chun, Joubert Aurélie, Op De Beeck Anne, Freida Delphine, Lemonnier François, Kieny Marie Paule, Inchauspé Geneviève

机构信息

Unité Mixte CNRS-BioMérieux, UMR 2142, Ecole Normale Supérieure, 46 Allée d'Italie, 69364 Lyon Cédex 07, France.

出版信息

J Virol. 2002 Dec;76(24):12735-46. doi: 10.1128/jvi.76.24.12735-12746.2002.

DOI:10.1128/jvi.76.24.12735-12746.2002
PMID:12438599
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC136695/
Abstract

A polyepitopic CD8(+)-T-cell response is thought to be critical for control of hepatitis C virus (HCV) infection. Using transgenic mice, we analyzed the immunogenicity and dominance of most known HLA-A2.1 epitopes presented during infection by using vaccines that carry the potential to enter clinical trials: peptides, DNA, and recombinant adenoviruses. The vaccines capacity to induce specific cytotoxic T lymphocytes and interferon gamma-producing cells revealed that immunogenic epitopes are clustered in specific antigens. For two key antigens, flanking regions were shown to greatly enhance the scope of epitope recognition, whereas a DNA-adenovirus prime-boost vaccination strategy augmented epitope immunogenicity, even that of subdominant ones. The present study reveals a clustered organization of HCV immunogenic HLA.A2.1 epitopes and strategies to modulate their dominance.

摘要

多表位CD8(+) T细胞应答被认为对丙型肝炎病毒（HCV）感染的控制至关重要。我们使用转基因小鼠，通过携带进入临床试验潜力的疫苗（肽、DNA和重组腺病毒），分析了感染期间呈现的大多数已知HLA - A2.1表位的免疫原性和优势性。这些疫苗诱导特异性细胞毒性T淋巴细胞和产生干扰素γ细胞的能力表明，免疫原性表位聚集在特定抗原中。对于两种关键抗原，侧翼区域被证明可大大扩大表位识别范围，而DNA - 腺病毒初免 - 加强疫苗接种策略增强了表位免疫原性，即使是亚优势表位的免疫原性。本研究揭示了HCV免疫原性HLA - A2.1表位的聚集组织以及调节其优势性的策略。