Tetramer enrichment reveals the presence of phenotypically diverse hepatitis C virus-specific CD8+ T cells in chronic infection

TY - JOUR

T1 - Tetramer enrichment reveals the presence of phenotypically diverse hepatitis C virus-specific CD8+ T cells in chronic infection

AU - Nitschke, Katja

AU - Flecken, Tobias

AU - Schmidt, Julia

AU - Gostick, Emma

AU - Marget, Matthias

AU - Neumann-Haefelin, Christoph

AU - Blum, Hubert E

AU - Price, David A

AU - Thimme, Robert

N1 - Copyright © 2015, Nitschke et al.

PY - 2015/1

Y1 - 2015/1

N2 - UNLABELLED: Virus-specific CD8(+) T cells are rarely detectable ex vivo by conventional methods during chronic hepatitis C virus (HCV) infection. In this study, however, we were able to detect and characterize HCV-specific CD8(+) T cells in all chronically HCV genotype 1a-infected, HLA-A*02:01-positive patients analyzed by performing major histocompatibility complex (MHC) class I tetramer enrichment. Two-thirds of these enriched HCV-specific CD8(+) T-cell populations displayed an effector memory phenotype, whereas, surprisingly, one-third displayed a naive-like phenotype despite ongoing viral replication. CD8(+) T cells with an effector memory phenotype could not expand in vitro, suggesting exhaustion of these cells. Interestingly, some of the naive-like CD8(+) T cells proliferated vigorously upon in vitro priming, whereas others did not. These differences were linked to the corresponding viral sequences in the respective patients. Indeed, naive-like CD8(+) T cells from patients with the consensus sequence in the corresponding T-cell epitope did not expand in vitro. In contrast, in patients displaying sequence variations, we were able to induce HCV-specific CD8(+) T-cell proliferation, which may indicate infection with a variant virus. Collectively, these data reveal the presence of phenotypically and functionally diverse HCV-specific CD8(+) T cells at very low frequencies that are detectable in all chronically infected patients despite viral persistence.IMPORTANCE: In this study, we analyzed CD8(+) T-cell responses specific for HLA-A*02:01-restricted epitopes in chronically HCV-infected patients, using MHC class I tetramer enrichment. Importantly, we could detect HCV-specific CD8(+) T-cell populations in all patients. To further characterize these HCV-specific CD8(+) T-cell populations that are not detectable using conventional techniques, we performed phenotypic, functional, and viral sequence analyses. These data revealed different mechanisms for CD8(+) T-cell failure in HCV infection, including T-cell exhaustion, viral escape, and functional impairment of naive-like HCV-specific CD8(+) T cells.

AB - UNLABELLED: Virus-specific CD8(+) T cells are rarely detectable ex vivo by conventional methods during chronic hepatitis C virus (HCV) infection. In this study, however, we were able to detect and characterize HCV-specific CD8(+) T cells in all chronically HCV genotype 1a-infected, HLA-A*02:01-positive patients analyzed by performing major histocompatibility complex (MHC) class I tetramer enrichment. Two-thirds of these enriched HCV-specific CD8(+) T-cell populations displayed an effector memory phenotype, whereas, surprisingly, one-third displayed a naive-like phenotype despite ongoing viral replication. CD8(+) T cells with an effector memory phenotype could not expand in vitro, suggesting exhaustion of these cells. Interestingly, some of the naive-like CD8(+) T cells proliferated vigorously upon in vitro priming, whereas others did not. These differences were linked to the corresponding viral sequences in the respective patients. Indeed, naive-like CD8(+) T cells from patients with the consensus sequence in the corresponding T-cell epitope did not expand in vitro. In contrast, in patients displaying sequence variations, we were able to induce HCV-specific CD8(+) T-cell proliferation, which may indicate infection with a variant virus. Collectively, these data reveal the presence of phenotypically and functionally diverse HCV-specific CD8(+) T cells at very low frequencies that are detectable in all chronically infected patients despite viral persistence.IMPORTANCE: In this study, we analyzed CD8(+) T-cell responses specific for HLA-A*02:01-restricted epitopes in chronically HCV-infected patients, using MHC class I tetramer enrichment. Importantly, we could detect HCV-specific CD8(+) T-cell populations in all patients. To further characterize these HCV-specific CD8(+) T-cell populations that are not detectable using conventional techniques, we performed phenotypic, functional, and viral sequence analyses. These data revealed different mechanisms for CD8(+) T-cell failure in HCV infection, including T-cell exhaustion, viral escape, and functional impairment of naive-like HCV-specific CD8(+) T cells.

KW - Adult

KW - Aged

KW - CD8-Positive T-Lymphocytes

KW - Cell Proliferation

KW - Female

KW - Hepacivirus

KW - Hepatitis C, Chronic

KW - Humans

KW - Immunologic Memory

KW - Male

KW - Middle Aged

KW - Phenotype

KW - T-Lymphocyte Subsets

KW - Young Adult

U2 - 10.1128/JVI.02242-14

DO - 10.1128/JVI.02242-14

M3 - SCORING: Journal article

C2 - 25320295

VL - 89

SP - 25

EP - 34

JO - J VIROL

JF - J VIROL

SN - 0022-538X

IS - 1

ER -