Background/Aims
While the adaptive immune response is crucial for spontaneous resolution of acute
hepatitis C virus (HCV) infection, it also constitutes the driving force for viral
escape. For acutely HCV-infected dialysis patients, little is known about the host
response and its impact on viral evolution.
Methods
Four haemodialysis patients accidentally infected with the same HCV strain were prospectively
investigated with respect to the clinical course, CD4+ and CD8+ T-cell responses,
neutralizing antibodies, viral kinetics and sequence variability.
Results
In one patient, a robust CD4+ T-cell response was associated with transient control
of infection, while in the other patients, weak responses correlated with persistently
high viremia. Despite the presence of CD8+ T-cell effectors in the first patient,
no sequence differences were detected in targeted regions of the viral genome in any
of the patients when viral persistence was established. Genetic stability in the envelope
genes, including the hypervariable regions, correlated with low-level or absent neutralizing
antibodies in all of the patients.
Conclusions
The establishment of viral persistence in the special patient group of dialysis patients
is due to a failure of the adaptive immune system, as shown by the absence of significant
T-cell and antibody responses, as well as viral variability.
Abbreviations:
HCV (hepatitis C virus), TH1 (T-helper cells type 1), RNA (ribonucleic acid), HVR1 (hypervariable region 1), ELISA (enzyme linked immuno sorbent assay), PCR (polymerase chain reaction), NS3 (non structural protein 3), NS4 (non structural protein 4), IFN-gamma (interferon-gamma), TNF-alpha (tumor necrosis factor-alpha), SD (standard deviation), PBMC (peripheral blood mononuclear cells), HCVpp (HCV pseudotype particles), GFP (green fluorescent protein), PE (post exposure), LC (local controls), ALT (alanine aminotransferase), HLA (human leukocyte antigen), HVR2 (hypervariable region 2)Keywords
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References
- Natural history of hepatitis C.Clin Liver Dis. 2005; 9: 383-398
- Determinants of viral clearance and persistence during acute hepatitis C virus infection.J Exp Med. 2001; 194: 1395-1406
- Immune evasion versus recovery after acute hepatitis C virus infection from a shared source.J Exp Med. 2005; 201: 1725-1731
- Frequencies of HCV-specific effector CD4+ T cells by flow cytometry: correlation with clinical disease stages.Hepatology. 2002; 35: 190-198
- High resolution analysis of cellular immune responses in resolved and persistent hepatitis C virus infection.Gastroenterology. 2004; 127: 924-936
- Early impairment of hepatitis C virus specific T cell proliferation during acute infection leads to failure of viral clearance.Gut. 2006; 55: 1012-1019
- Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease.Proc Natl Acad Sci USA. 2002; 99: 15661-15668
- Outcome of acute hepatitis C is related to virus-specific CD4 function and maturation of antiviral memory CD8 responses.Hepatology. 2006; 44: 126-139
- Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T-cell response in acute hepatitis C.Gastroenterology. 1999; 117: 933-941
- Transient immunological control during acute hepatitis C virus infection: ex vivo analysis of helper T-cell responses.J Viral Hepat. 2006; 13: 708-714
- Prospective study of viral clearance and CD4(+) T-cell response in acute hepatitis C primary infection and reinfection.J Clin Virol. 2006; 36: 24-31
- Discordant role of CD4 T-cell response relative to neutralizing antibody and CD8 T-cell responses in acute hepatitis C.Gastroenterology. 2007; 132: 654-666
- Early antibody response against hypervariable region 1 is associated with acute self-limiting infections of hepatitis C virus.Hepatology. 1997; 25: 1245-1249
- Rapid induction of virus-neutralizing antibodies and viral clearance in a single-source outbreak of hepatitis C.Proc Natl Acad Sci USA. 2007; 104: 6025-6030
- CD8 epitope escape and reversion in acute HCV infection.J Exp Med. 2004; 200: 1593-1604
- Dominant influence of an HLA-B27 restricted CD8+ T cell response in mediating HCV clearance and evolution.Hepatology. 2006; 43: 563-572
- Cellular immune selection with hepatitis C virus persistence in humans.J Exp Med. 2005; 201: 1741-1752
- HCV persistence and immune evasion in the absence of memory T cell help.Science. 2003; 302: 659-662
- Hepatitis C virus continuously escapes from neutralizing antibody and T-cell responses during chronic infection in vivo.Gastroenterology. 2007; 132: 667-678
- The outcome of acute hepatitis C predicted by the evolution of the viral quasispecies.Science. 2000; 288: 339-344
- Acute hepatitis C virus structural gene sequences as predictors of persistent viremia: hypervariable region 1 as a decoy.J Virol. 1999; 73: 2938-2946
- High-resolution phylogenetic analysis of hepatitis C virus adaptation and its relationship to disease progression.J Virol. 2004; 78: 3447-3454
- Hepatitis C virus infection and the dialysis patient.Semin Dial. 2007; 20: 416-422
- Disturbances of acquired immunity in hemodialysis patients.Semin Dial. 2007; 20: 440-451
- Impaired T cell proliferation, increased soluble death-inducing receptors and activation-induced T cell death in patients undergoing haemodialysis.Clin Exp Immunol. 2001; 125: 142-148
- Signalling via the TCR/CD3 antigen receptor complex in uremia is limited by the receptors number.Nephron. 1993; 64: 369-375
- Hepatitis B vaccine in patients receiving hemodialysis. Immunogenicity and efficacy.N Engl J Med. 1984; 311: 496-501
- Influenza subtype-specific IgA, IgM and IgG responses in patients on hemodialysis after influenza vaccination.Infection. 1988; 16: 323-328
- Avoiding false positives with PCR.Nature. 1989; 339: 237-238
- Molecular evolutionary analysis. Its application in the study of hepatitis C virus.in: Lau J.Y.N. Hepatitis C protocols. Humana Press, Totowa1998: 147-158
Felsenstein J. PHYLIP (Phylogenetic Inference Package). Available from: http://evolution.gs.washington.edu/phylip.html. Accessed November 2006.
- Virological and immunological determinants of intrahepatic virus-specific CD8+ T-cell failure in chronic hepatitis C virus infection.Hepatology. 2008; 47: 1824-1836
- Viral and cellular determinants of the hepatitis C virus envelope-heparan sulfate interaction.J Virol. 2006; 80: 10579-10590
- Characterization of an immunologically conserved epitope from hepatitis C virus E2 glycoprotein recognized by HLA-A2 restricted cytotoxic T lymphocytes.J Hepatol. 2001; 34: 321-329
- Liver-derived CTL in hepatitis C virus infection: breadth and specificity of responses in a cohort of persons with chronic infection.J Immunol. 1998; 160: 1479-1488
- Detection of diverse hepatitis C virus (HCV)-specific cytotoxic T lymphocytes in peripheral blood of infected persons by screening for responses to all translated proteins of HCV.J Virol. 2001; 75: 1229-1235
- Hepatitis C virus-specific cytolytic T lymphocyte and T helper cell responses in seronegative persons.J Infect Dis. 1997; 176: 859-866
- HLA class I-restricted cytotoxic T lymphocytes specific for hepatitis C virus. Identification of multiple epitopes and characterization of patterns of cytokine release.J Clin Invest. 1995; 96: 2311-2321
- Presence of effector CD8+ T cells in hepatitis C virus-exposed healthy seronegative donors.J Immunol. 1999; 162: 6681-6689
- Virus-specific CD8(+) T cells with type 1 or type 2 cytokine profile are related to different disease activity in chronic hepatitis C virus infection.Eur J Immunol. 2001; 31: 894-906
- Differential cytotoxic T-lymphocyte responsiveness to the hepatitis B and C viruses in chronically infected patients.J Virol. 1996; 70: 7092-7102
- Quantitative analysis of the peripheral blood cytotoxic T lymphocyte response in patients with chronic hepatitis C virus infection.J Clin Invest. 1996; 98: 1432-1440
- Cellular immune responses persist and humoral responses decrease two decades after recovery from a single-source outbreak of hepatitis C.Nat Med. 2000; 6: 578-582
- Production of interleukin-2 in response to synthetic peptides from hepatitis C virus E1 protein in patients with chronic hepatitis C: relationship with the response to interferon treatment.J Hepatol. 1996; 25: 1-9
- Distinct MHC class I and II alleles are associated with hepatitis C viral clearance, originating from a single source.Hepatology. 2004; 40: 108-114
- Spontaneous resolution of chronic hepatitis C virus disease after withdrawal of immunosuppression.Gastroenterology. 2003; 124: 1946-1949
- Human serum facilitates hepatitis C virus infection, and neutralizing responses inversely correlate with viral replication kinetics at the acute phase of hepatitis C virus infection.J Virol. 2005; 79: 6023-6034
- Humoral immune responses in uremia and the role of IL-10.Blood Purif. 2002; 20: 485-488
- Comparison of the rate of sequence variation in the hypervariable region of E2/NS1 region of hepatitis C virus in normal and hypogammaglobulinemic patients.Hepatology. 1998; 27: 223-227
- Novel CD4+ and CD8+ T-cell determinants within the NS3 protein in subjects with spontaneously resolved HCV infection.Hepatology. 2003; 37: 577-589
Article info
Publication history
Published online: January 27, 2009
Accepted:
November 24,
2008
Received in revised form:
November 6,
2008
Received:
September 3,
2008
Associate Editor: V. BarnabaFootnotes
☆The authors declare that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this manuscript. The underlying research reported in the study was funded by the “Hochschuljubiläumsstiftung” of the city of Vienna, Austria (Project H1802/2006).
Identification
Copyright
© 2009 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
