title: Targeting naturally occurring epitope variants of hepatitis C virus with high-affinity T-cell receptors.
abstract: Hepatitis C virus (HCV) readily establishes chronic infection, which is characterized by failure of virus-specific CD8+ T cells. HCV uses epitope mutation and T-cell exhaustion to escape from the host immune response. Previously, we engineered high-affinity T-cell receptors (HATs) targeting human immunodeficiency virus escape mutants. In this study, the affinity of a T-cell receptor specific for the HLA-A2-restricted HCV immunodominant epitope NS3 1406-1415 (KLVALGINAV) was improved from a KD of 6.6 µM to 40 pM. These HATs could also target HCV NS3 naturally occurring variants, including an escape variant vrt1 (KLVVLGINAV), with high affinities. The HATs can be used as high-affinity targeting molecules at the centre of the immune synapse for the HLA-restricted NS3 antigen. By fusing the HAT with a T-cell activation molecule, an anti-CD3 single-chain variable fragment, we constructed a molecule called high-affinity T-cell activation core (HATac), which can redirect functional CTLs possessing any specificity to recognize and kill cells presenting HCV NS3 antigens. This capability was verified with T2 cells loaded with prototype or variant peptides and HepG2 cells expressing the truncated NS3 prototype or variant proteins. The results indicate that HATac targeting the HLA-restricted NS3 antigen may provide a useful tool for circumventing immune escape mutants and T-cell exhaustion caused by HCV infection.
authors.affiliation: State Key Lab of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, PR China.|Present address: Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, PR China.
authors.forename: Huajun
authors.initials: H
authors.lastname: Zhang
authors.affiliation: XiangXue Life Sciences Research Center, XiangXue Pharmaceutical Co. Ltd, Guangzhou, PR China.
authors.forename: Jianbing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: XiangXue Life Sciences Research Center, XiangXue Pharmaceutical Co. Ltd, Guangzhou, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: XiangXue Life Sciences Research Center, XiangXue Pharmaceutical Co. Ltd, Guangzhou, PR China.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Weng
authors.affiliation: State Key Lab of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, PR China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.affiliation: XiangXue Life Sciences Research Center, XiangXue Pharmaceutical Co. Ltd, Guangzhou, PR China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Zhao
authors.affiliation: State Key Lab of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, PR China.
authors.forename: Youjia
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Lab of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, PR China.
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.affiliation: State Key Lab of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, PR China.
authors.forename: Zhaoduan
authors.initials: Z
authors.lastname: Liang
authors.affiliation: XiangXue Life Sciences Research Center, XiangXue Pharmaceutical Co. Ltd, Guangzhou, PR China.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Zheng
authors.affiliation: XiangXue Life Sciences Research Center, XiangXue Pharmaceutical Co. Ltd, Guangzhou, PR China.
authors.forename: Wenzhuo
authors.initials: W
authors.lastname: Zhao
authors.affiliation: XiangXue Life Sciences Research Center, XiangXue Pharmaceutical Co. Ltd, Guangzhou, PR China.
authors.forename: Shi
authors.initials: S
authors.lastname: Zhong
authors.affiliation: State Key Lab of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, PR China.|XiangXue Life Sciences Research Center, XiangXue Pharmaceutical Co. Ltd, Guangzhou, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
mesh_terms: D017252:CD3 Complex / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D014644:Genetic Variation; D057809:HEK293 Cells; D015789:HLA-A2 Antigen / Q000276:immunology; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000276:immunology*; D018963:Hepatitis Antigens / Q000235:genetics / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D057127:Single-Chain Antibodies / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000276:immunology*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D017252:CD3 Complex; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D018963:Hepatitis Antigens; D016056:Immunodominant Epitopes; D011948:Receptors, Antigen, T-Cell; D057127:Single-Chain Antibodies; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases