RT Journal Article SR Electronic(1) A1 Zhang, Huajun A1 Zhang, Jianbing A1 Chen, Lei A1 Weng, Zhiming A1 Tian, Ye A1 Zhao, Haifeng A1 Li, Youjia A1 Chen, Lin A1 Liang, Zhaoduan A1 Zheng, Hongjun A1 Zhao, Wenzhuo A1 Zhong, Shi A1 Li, YiYR 2017 T1 Targeting naturally occurring epitope variants of hepatitis C virus with high-affinity T-cell receptors JF Journal of General Virology, VO 98 IS 3 SP 374 OP 384 DO https://doi.org/10.1099/jgv.0.000656 PB Microbiology Society, SN 1465-2099, AB 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., UL https://www.microbiologyresearch.org/content/journal/jgv/10.1099/jgv.0.000656