Hepatitis C virus variants circumventing cytotoxic T lymphocyte activity as a mechanism of chronicity

doi:10.1016/S0016-5085(98)70268-9

Gastroenterology

Volume 115, Issue 4, October 1998, Pages 954-966

Presented in part at the 3rd International Meeting on Hepatitis C Virus and Related Viruses in September 1995 in Gold Coast, Australia, and at the Congress of Molecular Medicine in May 1997, Berlin, Germany, and published in abstract form (J Mol Med 1997;75:B70).

https://doi.org/10.1016/S0016-5085(98)70268-9 Get rights and content

Abstract

Background & Aims: High rate of chronicity after acute hepatitis C virus (HCV) infection cannot be explained in the presence of a multispecific cytotoxic T lymphocyte (CTL) response. The aim of this study was to investigate the effect of virus variants on CTL activity in patients in whom chronicity developed. Methods: CTL clones specific to a decapeptide epitope derived from hypervariable region 1 were generated from 5 HLA-A₂–positive patients with acute hepatitis C by in vitro stimulation with synthetic peptides. The sequential change of this CTL epitope and its influence on the CTL recognition were examined. Results: Virus variants did not appear in 3 patients with recovery, whereas variants with altered peptide ligands capable of antagonizing CTL activity emerged rapidly in the remaining 2 patients in whom chronicity developed. Importantly, these HLA-A₂–restricted, hypervariable region 1–specific CTL clones shared the use of T-cell receptor (TCR) genes AV6 and BV17. Conclusions: These data suggest that there is only a narrow T-cell repertoire responding to a single viral peptide/HLA ligand. The emergence of HCV variants with altered peptide ligands as TCR antagonists accompanied by a limited TCR repertoire may provide a mechanism for HCV chronicity.

GASTROENTEROLOGY 1998;115:954-966

Section snippets

Patients

The demographic data of the patients and control subjects studied are listed in Table 1.

. Characteristics of subjects

Patients	Age (yr)/sex	HLA typing (class I)	Peak ALT (U/L)^a	HCV-PCR (genotype)^b	Evolution
Hepatitis C patients
HCV1	53/M	A2 A11 B13 B46 Cw1 Cw10	1178	Positive (1a + 1b)	Chronicity
HCV2	60/F	A2 A24 B13 B61 Cw3	871	Positive (1b)	Recovery
HCV3	46/M	A2 A24 B13 B48 Cw10	749	Positive (1b)	Chronicity
HCV4	41/M	A2 A11 B58 B60 Cw4 Cw10	448	Positive (1b)	Recovery
HCV5	44/M	A2 A24 B75 B15 Cw9 Cw7	1830	Positive (1b)	Recovery

HVR1 variations in acute-phase serum samples of different subjects

The HVR1 (amino acids 384-407) sequences from acute-phase serum samples of the 5 patients reveal a significant variation in amino acid residues isolated from different time points (data not provided). Because the decapeptides (amino acids 398-407) of HVR1 had a predominantly positive response to HLA-A₂ stabilization assay (Table 2), it is most likely that a T-cell epitope exists.²⁸ The sequence variation of this region is shown in Figure 2.

. Amino acid (398-407) sequences of HVR1 deduced from

Discussion

We generated HLA-A₂–restricted CTL clones from PBMCs and liver infiltrates of a liver biopsy sample from HLA-A₂–positive patients with acute HCV. The CTL clones are specific to a decapeptide epitope in HVR1. The CTLp directed to this epitope was significantly higher in patients in recovery than those with chronicity. Follow-up study in 2 patients in whom chronicity developed showed that they had a conversion from a prototype to a mutant type in this epitope. These mutant peptides can function

Acknowledgements

The authors thank Drs. J. H. Ou and S. Y. Lo of the University of Southern California, Los Angeles, California, and Tzu Chi College of Medicine, Hualien, Taiwan, respectively, for providing the hepatitis C virus–expressing plasmid cytomegalovirus-RCEβ; S. N. Huang of the University of Toronto, Canada, for critical reading of the manuscript; S. K. Lo of Deakin University, Burwood, Australia, for statistical assessement of precursor frequency of cytotoxic T lymphocyte; and S. C. Chu and S. C. Chi

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^☆: Address requests for reprints to: Sun-Lung Tsai, M.D., Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan 105. Fax: (886) 2-3-3282824.

^☆☆: Supported by grants from the Department of Health (DOH85HR-522), the National Science Council (NSC 86-2315-B-182-003 and 84-2331-B182-049), and the Prosperous Foundation, Taipei, Taiwan.

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Liver, Pancreas, and Biliary TractHepatitis C virus variants circumventing cytotoxic T lymphocyte activity as a mechanism of chronicity☆,☆☆

Abstract

Section snippets

Patients

HVR1 variations in acute-phase serum samples of different subjects

Discussion

Acknowledgements

Blood

Semin Virol

Cell

Gastroenterology

Hepatology

Virology

Virology

Virology

Cell

Immunity

Lancet

Cell

Immunol Today

Lancet

Gastroenterology

Cell

Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome

Science

An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis

Science

The natural history of community-acquired hepatitis C in the United States

N Engl J Med

Virus escape from CTL recognition

J Exp Med

Persistent hepatitis C virus infection in a chimpanzee is associated with emergence of a cytotoxic T lymphocyte escape variant

Proc Natl Acad Sci USA

Detection of type 2–like T helper cells in hepatitis C virus (HCV) infection: implications for HCV chronicity

Hepatology

Purification and characterization of a naturally processed hepatitis B virus peptide recognized by CD8+ cytotoxic T lymphocytes

J Clin Invest

Typing hepatitis C virus by polymerase chain reaction with type-specific primers: applications to clinical surveys and tracing infectious sources

J Gen Virol

DNA sequence analysis with a modified bacterophage T7 DNA polymerase

Proc Natl Acad Sci USA

Hepatitis C virus (HCV) circulates as a population of different but closely related genomes: quasispecies nature of HCV genome distribution

J Virol

Lack of protective immunity against reinfection with hepatitis C virus

Science

Genetic organization and diversity of the hepatitis C virus

Proc Natl Acad Sci USA

Molecular cloning of human hepatitis C virus genome from Japanese patients with non-A, non-B hepatitis

Proc Natl Acad Sci USA

Development of a lipopeptide based therapeutic vaccine to treat chronic HBV infection. 1. Induction of a primary cytotoxic T lymphocyte response in humans

J Clin Invest

Characterization of T cell clones specific to a determinant of hepatitis B virus core and e antigens in chronic type B hepatitis: implication for T cell mechanism of HBV immunopathogenesis

J Biomed Sci

Analysis of rearranged T cell receptor (TCR) Vβ transcripts in livers of primary biliary cirrhosis: preferential Vβ usage suggests antigen-driven selection

Clin Exp Immunol

Limiting dilution assays for the determination of immunocompetent cell frequencies. I. Data analysis

J Immunol

Acute exacerbations of chronic type B hepatitis are accompanied by increased T cell responses to hepatitis B core and e antigens

J Clin Invest

The relationship between class I binding affinity and immunogenicity of potential cytotoxic T cell epitopes

J Immunol

Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules

Nature

Liver, Pancreas, and Biliary Tract
Hepatitis C virus variants circumventing cytotoxic T lymphocyte activity as a mechanism of chronicity☆,☆☆

Purification and characterization of a naturally processed hepatitis B virus peptide recognized by CD8⁺ cytotoxic T lymphocytes