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Semin Liver Dis 2005; 25(1): 7-17
DOI: 10.1055/s-2005-864778
Published in 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001 USA.

Acute Hepatitis C: A Multifaceted Disease

Theo Heller1 , Barbara Rehermann1 , 2
  • 1Liver Diseases Branch, NIDDK, National Institutes of Health, Bethesda, Maryland
  • 2Senior Investigator
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Publication History

Publication Date:
25 February 2005 (online)

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Abstract

Although acute hepatitis C virus (HCV) infection is a rare disease and typically not associated with severe clinical symptoms, it has become a disease of significant interest for clinical investigators, virologists, and immunologists alike. In the same way that acute hepatitis C provided a window of opportunity for understanding the clinical and virological aspects of HCV infection as the field was being established, it is now clear that it can provide a window into further understanding the early interaction of the virus with the host immune response. The acute phase of infection is usually considered to be the first 6 months; however, rather than defining acute HCV by the time that has passed after initial infection, it can also be defined as the biological state in which spontaneous clearance is still possible.

KEYWORDS

Acute - liver - hepatitis C virus - treatment - interferon - T cell - immune response

REFERENCES

  • 1 Alter M J, Hadler S C, Judson F N et al.. Risk factors for acute non-A, non-B hepatitis in the United States and association with hepatitis C virus antibody.  JAMA. 1990;  264 2231-2235
    CrossrefPubMedGoogle Scholar
  • 2 Alter H J, Purcell R H, Shih J W et al.. Detection of antibody to hepatitis C virus in prospectively followed transfusion recipients with acute and chronic non-A, non-B hepatitis.  N Engl J Med. 1989;  321 1494-1500
    CrossrefPubMedGoogle Scholar
  • 3 Schlauder G G, Leverenz G J, Amann C W et al.. Detection of the hepatitis C virus genome in acute and chronic experimental infection in chimpanzees.  J Clin Microbiol. 1991;  29 2175-2179
    PubMedGoogle Scholar
  • 4 Alberti A, Boccato S, Vario A, Benvegnu L. Therapy of acute hepatitis C.  Hepatology. 2002;  36 S195-S200
    CrossrefPubMedGoogle Scholar
  • 5 Alberti A, Chemello L, Benvegnu L. Natural history of hepatitis C.  J Hepatol. 1999;  31(Suppl 1) 17-24
    PubMedGoogle Scholar
  • 6 Villano S A, Vlahov D, Nelson K E et al.. Persistence of viremia and the importance of long-term follow-up after acute hepatitis C infection.  Hepatology. 1999;  29 908-914
    CrossrefPubMedGoogle Scholar
  • 7 Thomas D L, Astemborski J, Rai R M et al.. The natural history of hepatitis C virus infection: host, viral, and environmental factors.  JAMA. 2000;  284 450-456
    CrossrefPubMedGoogle Scholar
  • 8 Gerlach J T, Diepolder H M, Zachoval R et al.. Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance.  Gastroenterology. 2003;  125 80-88
    CrossrefPubMedGoogle Scholar
  • 9 Hofer H, Watkins-Riedel T, Janata O et al.. Spontaneous viral clearance in patients with acute hepatitis C can be predicted by repeated measurements of serum viral load.  Hepatology. 2003;  37 60-64
    CrossrefPubMedGoogle Scholar
  • 10 Larghi A, Zuin M, Crosignani A et al.. Outcome of an outbreak of acute hepatitis C among healthy volunteers participating in pharmacokinetics studies.  Hepatology. 2002;  36 993-1000
    PubMedGoogle Scholar
  • 11 Bigger C B, Brasky K M, Lanford R E. DNA microarray analysis of chimpanzee liver during acute resolving hepatitis C virus infection.  J Virol. 2001;  75 7059-7066
    CrossrefPubMedGoogle Scholar
  • 12 Rahman F, Heller T, Sobao Y et al.. Effects of antiviral therapy on the cellular immune response in acute hepatitis C.  Hepatology. 2004;  40 87-97
    CrossrefPubMedGoogle Scholar
  • 13 Lefrere J J, Roudot-Thoraval F, Lunel F et al.. Expertise of French laboratories in detection, genotyping, and quantification of hepatitis C virus RNA in serum.  J Clin Microbiol. 2004;  42 2027-2030
    CrossrefPubMedGoogle Scholar
  • 14 Pawlotsky J M. Diagnostic testing in hepatitis C virus infection: viral kinetics and genomics.  Semin Liver Dis. 2003;  23(suppl 1) 3-11
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Krogsgaard K, Wantzin P, Mathiesen L R et al.. Early appearance of antibodies to hepatitis C virus in community acquired acute non-A, non-B hepatitis is associated with progression to chronic liver disease. The Copenhagen Hepatitis Acuta Programme.  Scand J Infect Dis. 1990;  22 399-402
    PubMedGoogle Scholar
  • 16 Kryczka W, Walewska-Zielecka B, Dutkiewicz E. Acute seronegative hepatitis C manifesting itself as adult giant cell hepatitis-a case report and review of literature.  Med Sci Monit. 2003;  9(Suppl 3) 29-31
    PubMedGoogle Scholar
  • 17 Morand P, Dutertre N, Minazzi H et al.. Lack of seroconversion in a health care worker after polymerase chain reaction-documented acute hepatitis C resulting from a needlestick injury.  Clin Infect Dis. 2001;  33 727-729
    CrossrefPubMedGoogle Scholar
  • 18 Seeff L B, Hollinger F B, Alter H J et al.. Long-term mortality and morbidity of transfusion-associated non-A, non-B, and type C hepatitis: A National Heart, Lung, and Blood Institute collaborative study.  Hepatology. 2001;  33 455-463
    CrossrefPubMedGoogle Scholar
  • 19 Takaki A, Wiese M, Maertens G et al.. Cellular immune responses persist, humoral responses decrease two decades after recovery from a single source outbreak of hepatitis C.  Nat Med. 2000;  6 578-582
    PubMedGoogle Scholar
  • 20 Cerny A, McHutchison J G, Pasquinelli C et al.. Cytotoxic T lymphocyte response to hepatitis C virus-derived peptides containing the HLA A2.1 binding motif.  J Clin Invest. 1995;  95 521-530
    PubMedGoogle Scholar
  • 21 Rehermann B, Chang K M, McHutchison J G et al.. Quantitative analysis of the peripheral blood cytotoxic T lymphocyte response, disease activity and viral load in patients with chronic hepatitis C virus infection.  J Clin Invest. 1996;  98 1432-1440
    PubMedGoogle Scholar
  • 22 Rehermann B, Chang K M, McHutchison J et al.. Differential cytotoxic T lymphocyte responsiveness to the hepatitis B and C viruses in chronically infected patients.  J Virol. 1996;  70 7092-7102
    PubMedGoogle Scholar
  • 23 Chang K M, Gruener N H, Southwood S et al.. Identification of HLA-A3 and -B7-restricted CTL response to hepatitis C virus in patients with acute and chronic hepatitis C.  J Immunol. 1999;  162 1156-1164
    PubMedGoogle Scholar
  • 24 Lauer G M, Ouchi K, Chung R T et al.. Comprehensive analysis of CD8( + )-T-cell responses against hepatitis C virus reveals multiple unpredicted specificities.  J Virol. 2002;  76 6104-6113
    CrossrefPubMedGoogle Scholar
  • 25 Lauer G M, Barnes E, Lucas M et al.. High resolution analysis of cellular immune responses in resolved and persistent hepatitis C virus infection.  Gastroenterology. 2004;  127 924-936
    PubMedGoogle Scholar
  • 26 Lechner F, Wong D K, Dunbar P R et al.. Analysis of successful immune responses in persons infected with hepatitis C virus.  J Exp Med. 2000;  191 1499-1512
    CrossrefPubMedGoogle Scholar
  • 27 Wedemeyer H, He X -S, Nascimbeni M et al.. Impaired effector function of hepatitis C virus-specific CD8 + T cells in chronic hepatitis C virus infection.  J Immunol. 2002;  169 3447-3458
    PubMedGoogle Scholar
  • 28 Su A I, Pezacki J P, Wodicka L et al.. Genomic analysis of the host response to hepatitis C virus infection.  Proc Natl Acad Sci USA. 2002;  99 15669-15674
    CrossrefPubMedGoogle Scholar
  • 29 Khakoo S I, Thio C L, Martin M P et al.. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection.  Science. 2004;  305 872-874
    CrossrefPubMedGoogle Scholar
  • 30 Diepolder H M, Zachoval R, Hoffmann R M et al.. Possible mechanism involving T lymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection.  Lancet. 1995;  346 1006-1007
    CrossrefPubMedGoogle Scholar
  • 31 Diepolder H M, Gerlach J -T, Zachoval R et al.. Immunodominant CD4 + T-cell epitope within nonstructural protein 3 in acute hepatitis C virus infection.  J Virol. 1997;  71 6011-6019
    PubMedGoogle Scholar
  • 32 Missale G, Bertoni R, Lamonaca V et al.. Different clinical behaviors of acute hepatitis C virus infection are associated with different vigor of the anti-viral cell-mediated immune response.  J Clin Invest. 1996;  98 706-714
    PubMedGoogle Scholar
  • 33 Lamonaca V, Missale G, Urbani S et al.. Conserved hepatitis C virus sequences are highly immunogenic for CD4( + ) T cells: implications for vaccine development.  Hepatology. 1999;  30 1088-1098
    CrossrefPubMedGoogle Scholar
  • 34 Gerlach J T, Diepolder H M, Jung M C et al.. Recurrence of hepatitis C virus after loss of virus-specific CD4( + ) T-cell response in acute hepatitis C.  Gastroenterology. 1999;  117 933-941
    CrossrefPubMedGoogle Scholar
  • 35 Thimme R, Oldach D, Chang K M et al.. Determinants of viral clearance and persistence during acute hepatitis C virus infection.  J Exp Med. 2001;  194 1395-1406
    CrossrefPubMedGoogle Scholar
  • 36 Cooper S, Erickson A L, Adams E J et al.. Analysis of a successful immune response against hepatitis C virus.  Immunity. 1999;  10 439-449
    CrossrefPubMedGoogle Scholar
  • 37 Shoukry N, Grakoui A, Houghton M et al.. Memory CD8 + T cells are required for protection from persistent hepatitis C virus infection.  J Exp Med. 2003;  197 1645-1655
    CrossrefPubMedGoogle Scholar
  • 38 Gerlach T J, Diepolder H M, Gruener N H et al.. Symptomatic acute hepatitis C: when to treat?.  Hepatology. 1999;  30 195A
    PubMedGoogle Scholar
  • 39 Farci P, Alter H J, Wong D C et al.. Prevention of hepatitis C virus infection in chimpanzees after antibody- mediated in vitro neutralization.  Proc Natl Acad Sci USA. 1994;  91 7792-7796
    PubMedGoogle Scholar
  • 40 Adams G, Kuntz S, Rabalais G et al.. Natural recovery from acute hepatitis C virus infection by agammaglobulinemic twin children.  Pediatr Infect Dis J. 1997;  16 533-534
    CrossrefPubMedGoogle Scholar
  • 41 Christie J M, Healey C J, Watson J et al.. Clinical outcome of hypogammaglobulinaemic patients following outbreak of acute hepatitis C: 2 year follow up.  Clin Exp Immunol. 1997;  110 4-8
    CrossrefPubMedGoogle Scholar
  • 42 Baumert T F, Wellnitz S, Aono S et al.. Antibodies against hepatitis C virus-like particles and viral clearance in acute and chronic hepatitis C.  Hepatology. 2000;  32 610-617
    CrossrefPubMedGoogle Scholar
  • 43 Bartosch B, Dubuisson J, Cosset F L. Infectious hepatitis C virus pseudo-particles containing functional E1-E2 envelope protein complexes.  J Exp Med. 2003;  197 633-642
    CrossrefPubMedGoogle Scholar
  • 44 Hsu M, Zhang J, Flint M et al.. Hepatitis C virus glycoproteins mediate pH-dependent cell entry of pseudotyped retroviral particles.  Proc Natl Acad Sci USA. 2003;  100 7271-7276
    CrossrefPubMedGoogle Scholar
  • 45 Logvinoff C, Major M E, Oldach D et al.. Neutralizing antibody response during acute and chronic hepatitis C virus infection.  Proc Natl Acad Sci USA. 2004;  101 10149-10154
    CrossrefPubMedGoogle Scholar
  • 46 Farci P, Shimoda A, Coiana A et al.. The outcome of acute hepatitis C predicted by the evolution of the viral quasispecies.  Science. 2000;  288 339-344
    CrossrefPubMedGoogle Scholar
  • 47 Fitzgerald K A, McWhirter S M, Faia K L et al.. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway.  Nat Immunol. 2003;  4 491-496
    CrossrefPubMedGoogle Scholar
  • 48 Yoneyama M, Kikuchi M, Natsukawa T et al.. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses.  Nat Immunol. 2004;  5 730-737
    CrossrefPubMedGoogle Scholar
  • 49 Balachandran S, Thomas E, Barber G N. A FADD-dependent innate immune mechanism in mammalian cells.  Nature. 2004;  432 401-405
    CrossrefPubMedGoogle Scholar
  • 50 Foy E, Li K, Wang C et al.. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease.  Science. 2003;  300 1145-1148
    CrossrefPubMedGoogle Scholar
  • 51 Taylor D R, Shi S T, Romano P R et al.. Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein.  Science. 1999;  285 107-110
    CrossrefPubMedGoogle Scholar
  • 52 Gale M J, Korth M J, Katze M G. Repression of the PKR protein kinase by the hepatitis C virus NS5A protein: a potential mechanism of interferon resistance.  Clin Diagn Virol. 1998;  10 157-162
    CrossrefPubMedGoogle Scholar
  • 53 Crotta S, Stilla A, Wack A et al.. Inhibition of natural killer cells through engagement of CD81 by the major hepatitis C Virus envelope protein.  J Exp Med. 2002;  195 35-42
    PubMedGoogle Scholar
  • 54 Tseng C T, Klimpel G R. Binding of the hepatitis C virus envelope protein E2 to CD81 inhibits natural killer cell functions.  J Exp Med. 2002;  195 43-49
    CrossrefPubMedGoogle Scholar
  • 55 Spada E, Mele A, Berton A et al.. Multispecific T cell response and negative HCV RNA tests during acute HCV infection are early prognostic factors of spontaneous clearance.  Gut. 2004;  53 1673-1681
    CrossrefPubMedGoogle Scholar
  • 56 Pham T N, MacParland S A, Mulrooney P M et al.. Hepatitis C virus persistence after spontaneous or treatment-induced resolution of hepatitis C.  J Virol. 2004;  78 5867-5874
    CrossrefPubMedGoogle Scholar
  • 57 Nascimbeni M, Mizukoshi E, Bosmann M et al.. Kinetics of CD4 + and CD8 + memory T cell responses during hepatitis C virus rechallenge of previously recovered chimpanzees.  J Virol. 2003;  77 4781-4793
    CrossrefPubMedGoogle Scholar
  • 58 Timm J, Lauer G, Kavanagh D G et al.. CTL escape and reversion in acute HCV infection.  J Exp Med. 2004;  200 1593-1604
    CrossrefPubMedGoogle Scholar
  • 59 Erickson A L, Kimura Y, Igarashi S et al.. The outcome of hepatitis C virus infection is predicted by escape mutations in epitopes targeted by cytotoxic T lymphocytes.  Immunity. 2001;  15 883-895
    CrossrefPubMedGoogle Scholar
  • 60 Seifert U, Liermann H, Racanelli V et al.. Hepatitis C virus mutation affects proteasomal epitope processing.  J Clin Invest. 2004;  114 250-259
    CrossrefPubMedGoogle Scholar
  • 61 Chang K M, Rehermann B, McHutchison J G et al.. Immunological significance of cytotoxic T lymphocyte epitope variants in patients chronically infected by the hepatitis C virus.  J Clin Invest. 1997;  100 2376-2385
    CrossrefPubMedGoogle Scholar
  • 62 Tsai S L, Chen Y M, Chen M H et al.. Hepatitis C virus variants circumventing cytotoxic T lymphocyte activity as a mechanism of chronicity.  Gastroenterology. 1998;  115 954-965
    CrossrefPubMedGoogle Scholar
  • 63 Valitutti S, Müller S, Cella M et al.. Serial triggering of many T-cell receptors by a few peptide-MHC complexes.  Nature. 1995;  375 148-151
    CrossrefPubMedGoogle Scholar
  • 64 Moore C B, John M, James I R et al.. Evidence of HIV-1 adaptation to HLA-restricted immune responses at a population level.  Science. 2002;  296 1439-1443
    CrossrefPubMedGoogle Scholar
  • 65 Allen T M, Altfeld M, Yu X G et al.. Selection, transmission, and reversion of an antigen-processing cytotoxic T-lymphocyte escape mutation in human immunodeficiency virus type 1 infection.  J Virol. 2004;  78 7069-7078
    CrossrefPubMedGoogle Scholar
  • 66 Frasca L, Del Porto P, Tuosto L et al.. Hypervariable region 1 variants act as TCR antagonists for hepatitis C virus-specific CD4 + T cells.  J Immunol. 1999;  163 650-658
    PubMedGoogle Scholar
  • 67 Shimizu Y K, Hijikita M, Iwamoto A et al.. Neutralizing antibodies against hepatitis C virus and the emergence of neutralization escape mutant viruses.  J Virol. 1994;  68 1494-1500
    PubMedGoogle Scholar
  • 68 Appay V, Dunbar P R, Callan M et al.. Memory CD8 + T cells vary in differentiation phenotype in different persistent virus infections.  Nat Med. 2002;  8 379-385
    CrossrefPubMedGoogle Scholar
  • 69 Francavilla V, Accapezzato D, De Salvo M et al.. Subversion of effector CD8 + T cell differentiation in acute hepatitis C virus infection: exploring the immunological mechanisms.  Eur J Immunol. 2004;  34 427-437
    CrossrefPubMedGoogle Scholar
  • 70 Koziel M J, Dudley D, Wong J T et al.. Intrahepatic cytotoxic T lymphocytes specific for hepatitis C virus in persons with chronic hepatitis.  J Immunol. 1992;  149 3339-3344
    PubMedGoogle Scholar
  • 71 Koziel J M, Dudley D, Afdhal N et al.. Hepatitis C virus (HCV)-specific cytotoxic T lymphocytes recognize epitopes in the core and envelope proteins of HCV.  J Virol. 1993;  67 7522-7532
    PubMedGoogle Scholar
  • 72 Koziel M J, Dudley D, Afdhal N et al.. 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
    PubMedGoogle Scholar
  • 73 Koziel M J, Walker B D. Characteristics of the intrahepatic cytotoxic T lymphocyte response in chronic hepatitis C virus infection.  Springer Semin Immunopathol. 1997;  19 69-83
    CrossrefPubMedGoogle Scholar
  • 74 Diepolder H M, Zachoval R, Hoffmann R M et al.. The role of hepatitis C virus specific CD4 + T lymphocytes in acute and chronic hepatitis C.  J Mol Med. 1996;  74 583-588
    CrossrefPubMedGoogle Scholar
  • 75 Kittlesen D J, Chianese-Bullock K A, Yao Z Q et al.. Interaction between complement receptor gC1qR and hepatitis C virus core protein inhibits T-lymphocyte proliferation.  J Clin Invest. 2000;  106 1239-1249
    PubMedGoogle Scholar
  • 76 Eisen-Vandervelde A L, Waggoner S N, Yao Z Q et al.. Hepatitis C virus core selectively suppresses interleukin-12 synthesis in human macrophages by interfering with AP-1 activation.  J Biol Chem. 2004;  279 43479-43486
    CrossrefPubMedGoogle Scholar
  • 77 Yao Z Q, Ray S, Eisen-Vandervelde A et al.. Hepatitis C virus: immunosuppression by complement regulatory pathway.  Viral Immunol. 2001;  14 277-295
    CrossrefPubMedGoogle Scholar
  • 78 Camma C, Almasio P, Craxi A. Interferon as treatment for acute hepatitis C. A meta-analysis.  Dig Dis Sci. 1996;  41 1248-1255
    PubMedGoogle Scholar
  • 79 Quin J. Interferon therapy for acute hepatitis C viral infection-a review by meta-analysis.  Aust N Z J Med. 1997;  27 611-618
    PubMedGoogle Scholar
  • 80 Thevenot T, Regimbeau C, Ratziu V et al.. Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C in naive patients: 1999 update.  J Viral Hepat. 2001;  8 48-62
    CrossrefPubMedGoogle Scholar
  • 81 Poynard T, Regimbeau C, Myers R P et al.. Interferon for acute hepatitis C.  Cochrane Database Syst Rev. 2002;  (1) CD000369
    PubMedGoogle Scholar
  • 82 Jaeckel E, Cornberg M, Wedemeyer H et al.. Treatment of acute hepatitis C with interferon alfa-2b.  N Engl J Med. 2001;  345 1452-1457
    CrossrefPubMedGoogle Scholar
  • 83 Vogel W, Graziadei I, Umlauft F et al.. High-dose interferon-alpha2b treatment prevents chronicity in acute hepatitis C: a pilot study.  Dig Dis Sci. 1996;  41 81S-85S
    PubMedGoogle Scholar
  • 84 Licata A, Di Bona D, Schepis F et al.. When and how to treat acute hepatitis C?.  J Hepatol. 2003;  39 1056-1062
    CrossrefPubMedGoogle Scholar
  • 85 Kamal S M, Ismail A, Graham C S et al.. Pegylated interferon alpha therapy in acute hepatitis C: relation to hepatitis C virus-specific T cell response kinetics.  Hepatology. 2004;  39 1721-1731
    CrossrefPubMedGoogle Scholar
  • 86 Lauer G M, Lucas M, Ouchi K et al.. T cell responses during early therapy for HCV infection.  Hepatology. 2003;  38 354A
    PubMedGoogle Scholar
  • 87 Tester I A, Smyk-Pearson S, Dean S, Rosen H R. Acute hepatitis C infection following patellar tendon transplantation: immunologic correlates of recovery.  Hepatology. 2003;  38 358A
    PubMedGoogle Scholar
  • 88 Kaplan D, Sugimoto K, Ikeda F et al.. Differential mechanism of interferon-induced and spontaneous clearance of hepatitis C virus infection.  Hepatology. 2003;  38 357A
    PubMedGoogle Scholar
  • 89 Nomura H, Sou S, Tanimoto H et al.. Short-term interferon-alfa therapy for acute hepatitis C: a randomized controlled trial.  Hepatology. 2004;  39 1213-1219
    CrossrefPubMedGoogle Scholar
  • 90 Major M E, Dahari H, Mihalik K et al.. Hepatitis C virus kinetics and host responses associated with disease and outcome of infection in chimpanzees.  Hepatology. 2004;  39 1709-1720
    CrossrefPubMedGoogle Scholar

Barbara RehermannM.D. 

Liver Diseases Branch, NIDDK, National Institutes of Health

DHHS, Bldg. 10, Room 9B16, 10 Center Drive

Bethesda, MD 20892

Email: Rehermann@nih.gov