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J Virol. 2015 Jan;89(1):25-34. doi: 10.1128/JVI.02242-14. Epub 2014 Oct 15.

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

Author information

1
Department of Medicine II, University Hospital Freiburg, Freiburg, Germany Faculty of Biology, University of Freiburg, Freiburg, Germany.
2
Department of Medicine II, University Hospital Freiburg, Freiburg, Germany Faculty of Biology, University of Freiburg, Freiburg, Germany Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg, Germany.
3
Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.
4
Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.
5
Institute of Transfusion Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
6
Department of Medicine II, University Hospital Freiburg, Freiburg, Germany robert.thimme@uniklinik-freiburg.de.

Abstract

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.

Comment in

PMID:
25320295
PMCID:
PMC4301109
DOI:
10.1128/JVI.02242-14
[Indexed for MEDLINE]
Free PMC Article

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