Abstract
Hepatitis C Virus infections have a high propensity to induce lifelong persistent infections. A number of host and environmental variables have been shown to impact the rate of persistent infection and the outcome of interferon (IFN)-based therapies. This review briefly highlights a few of the relevant observations that have been made with regard to viral clearance. HCV infection induces a highly elevated interferon stimulated gene (ISG) response in the liver during both acute and chronic infections. The role of this response in containing the spread of the virus in the liver and in mounting an effective adaptive immune response is poorly understood. The fact that an elevated hepatic ISG response during chronic infection negatively correlates with the outcome of IFN therapy is counter-intuitive and remains to be explained satisfactorily. The failure of the T cell response to clear virus appears to reside in a deficiency in the CD4 T cell help leading to anergic CD8 T cells, which may also be related to whether the innate response properly orchestrates the adaptive T cell response early in infection. The importance of the innate response in the outcome of infection is illustrated by recent genome wide association studies revealing a remarkable correlation between genetic polymorphisms in IL28B (IFNλ3) and clearance of infected cells whether during acute infection or IFN therapy, yet the mechanisms by which IFNλ3 and other innate effectors influence HCV infection are currently poorly understood.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Bassett SE, Guerra B, Brasky K et al Protective immune response to hepatitis C virus in chimpanzees rechallenged following clearance of primary infection (2001) Hepatology 33: 1479–1487.
Bigger CB, Brasky KM, Lanford RE DNA microarray analysis of chimpanzee liver during acute resolving hepatitis C virus infection (2001) J Virol 75: 7059–7066.
Bigger CB, Guerra B, Brasky KM et al Intrahepatic gene expression during chronic hepatitis C virus infection in chimpanzees (2004) J Virol 78: 13779–13792.
Bowen DG, Walker CM Adaptive immune responses in acute and chronic hepatitis C virus infection (2005) Nature 436: 946–952.
Bukh J, Thimme R, Meunier JC et al Previously infected chimpanzees are not consistently protected against reinfection or persistent infection after reexposure to the identical hepatitis C virus strain (2008) J Virol 82: 8183–8195.
Butera D, Marukian S, Iwamaye AE et al Plasma chemokine levels correlate with the outcome of antiviral therapy in patients with hepatitis C (2005) Blood 106: 1175–1182.
Chen LM, Borozan I, Feld J et al Hepatic gene expression discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection (2005) Gastroenterology 128: 1437–1444.
Cooper S, Erickson AL, Adams EJ et al Analysis of a successful immune response against hepatitis C virus (1999) Immunity 10: 439–449.
Cox AL, Mosbruger T, Lauer GM et al Comprehensive analyses of CD8+ T cell responses during longitudinal study of acute human hepatitis C (2005a) Hepatology 42: 104–112.
Cox AL, Mosbruger T, Mao Q et al Cellular immune selection with hepatitis C virus persistence in humans (2005b) J Exp Med 201: 1741–1752.
Day CL, Kaufmann DE, Kiepiela P et al PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression (2006) Nature 443: 350–354.
Diago M, Castellano G, Garcia-Samaniego J et al Association of pretreatment serum interferon gamma inducible protein 10 levels with sustained virological response to peginterferon plus ribavirin therapy in genotype 1 infected patients with chronic hepatitis C (2006) Gut 55: 374–379.
Diepolder HM, Zachoval R, Hoffmann RM et al Possible mechanism involving T-lymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection (1995) Lancet 346: 1006–1007.
Enomoto N, Sakuma I, Asahina Y et al Interferon sensitivity determining sequence of the hepatitis C virus genome (1996) Hepatology 24: 460–461.
Feld JJ, Nanda S, Huang Y et al Hepatic gene expression during treatment with peginterferon and ribavirin: Identifying molecular pathways for treatment response (2007) Hepatology 46: 1548–1563.
Flisiak R, Feinman SV, Jablkowski M et al The cyclophilin inhibitor debio 025 combined with PEG IFN alpha 2a significantly reduces viral load in treatment-naive Hepatitis C patients (2009) Hepatology 49: 1460–1468.
Foy E, Li K, Sumpter R et al Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling (2005) Proc Natl Acad Sci U S A 102: 2986–2991.
Foy E, Li K, Wang CF et al Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease (2003) Science 300: 1145–1148.
Fuller MJ, Shoukry NH, Gushima T et al Selection-driven immune escape is not a significant factor in the failure of CD4 T cell responses in persistent hepatitis C virus infection (2010) Hepatology 51: 378–387.
Gale M, Blakely CM, Kwieciszewski B et al Control of PKR protein kinase by hepatitis C virus nonstructural 5A protein: molecular mechanisms of kinase regulation (1998) Mol Cell Biol 18: 5208–5218.
Ge D, Fellay J, Thompson AJ et al Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance (2009) Nature 461: 399–401.
Grakoui A, Shoukry NH, Woollard DJ et al HCV persistence and immune evasion in the absence of memory T cell help (2003) Science 302: 659–662.
Grakoui A, John Wherry E, Hanson HL et al Turning on the off switch: Regulation of anti-viral T cell responses in the liver by the PD-1/PD-L1 pathway (2006) J Hepatol 45: 468–472.
Helbig KJ, Ruszkiewicz A, Lanford RE et al Differential expression of the CXCR3 ligands in chronic hepatitis C virus (HCV) infection and their modulation by HCV in vitro (2009) J Virol 83: 836–846.
Huang Y, Feld JJ, Sapp RK et al Defective hepatic response to interferon and activation of suppressor of cytokine signaling 3 in chronic hepatitis C (2007) Gastroenterology 132: 733–744.
Kawai T, Takahashi K, Sato S et al IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction (2005) Nat Immunol 6: 981–988.
Kenny-Walsh E, Irish HRG Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin (1999) N Engl J Med 340: 1228–1233.
Khakoo SI, Thio CL, Martin MP et al HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection (2004) Science 305: 872–874.
Lagging M, Romero A, Westin J et al IP-10 predicts viral response and therapeutic outcome in difficult-to-treat patients With HCV genotype 1 infection (2006) Hepatology 44: 1617–1625.
Lanford RE The Chimpanzee model of HCV (2006). In: R. F. Schinazi, E. R. Schiff (Eds.), Framing The Knowledge of Viral Hepatitis. pp. 197–218.
Lanford RE, Guerra B, Bigger CB et al Lack of response to exogenous interferon-alpha in the liver of HCV chronically infected chimpanzees (2007) Hepatology 46: 999–1008.
Lanford RE, Guerra B, Chavez D et al Cross-genotype immunity to hepatitis C virus (2004) J Virol 78: 1575–1581.
Lanford RE, Guerra B, Lee H et al Genomic response to interferon-alpha in chimpanzees: Implications of rapid downregulation for hepatitis C kinetics (2006) Hepatology 43: 961–972.
Lanford RE, Hildebrandt-Eriksen ES, Petri A et al Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection (2010) Science 327: 198–201.
Lechner F, Wong DK, Dunbar PR et al Analysis of successful immune responses in persons infected with hepatitis C virus (2000) J Exp Med 191: 1499–1512.
Li K, Foy E, Ferreon JC et al Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF (2005) Proc Natl Acad Sci USA 102: 2992–2997.
Liang Y, Shilagard T, Xiao SY et al Visualizing hepatitis C virus infections in human liver by two-photon microscopy (2009) Gastroenterology 137: 1448–1458.
Lin W, Kim SS, Yeung E et al Hepatitis C Virus core protein blocks interferon signaling by interaction with the STAT1 SH2 domain (2006) J Virol 80: 9226–9235.
Major ME, Mihalik K, Puig M et al Previously infected and recovered chimpanzees exhibit rapid responses that control hepatitis C virus replication upon rechallenge (2002) J Virol 76: 6586–6595.
Marcello T, Grakoui A, Barba-Spaeth G et al Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics (2006) Gastroenterology 131: 1887–1898.
Mehta SH, Cox A, Hoover DR et al Protection against persistence of hepatitis C (2002) Lancet 359: 1478–1483.
Meylan E, Curran J, Hofmann K et al Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus (2005) Nature 437: 1167–1172.
Miller DM, Klucher KM, Freeman JA et al Interferon lambda as a potential new therapeutic for hepatitis C (2009) Ann N Y Acad Sci 1182: 80–87.
Nakamoto N, Kaplan DE, Coleclough J et al Functional restoration of HCV-specific CD8 T cells by PD-1 blockade is defined by PD-1 expression and compartmentalization (2008) Gastroenterology 134: 1927–1937, 1937.e 1–2.
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 (2003) J Virol 77: 4781–4793.
Neumann AU, Lam NP, Dahari H et al Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-α therapy (1998) Science 282: 103–107.
Osburn WO, Fisher BE, Dowd KA et al Spontaneous control of primary hepatitis C virus infection and immunity against persistent reinfection (2010) Gastroenterology 138: 315–324.
Polyak SJ, Khabar KSA, Paschal DM et al Hepatitis C virus nonstructural 5A protein induces interleukin-8, leading to partial inhibition of the interferon-induced antiviral response (2001) J Virol 75: 6095–6106.
Prince AM, Brotman B, Lee DH et al Protection against chronic hepatitis C virus infection after rechallenge with homologous, but not heterologous, genotypes in a chimpanzee model (2005) J Infect Dis 192: 1701–1709.
Radziewicz H, Ibegbu CC, Fernandez ML et al Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression (2007) J Virol 81: 2545–2553.
Rehermann B, Nascimbeni M Immunology of hepatitis B virus and hepatitis C virus infection (2005) Nat Rev Immunol 5: 215–229.
Robek MD, Boyd BS, Chisari FV Lambda interferon inhibits hepatitis B and C virus replication (2005) J Virol 79: 3851–3854.
Romero AI, Lagging M, Westin J et al Interferon (IFN)-[gamma]-inducible protein-10: association with histological results, viral kinetics, and outcome during treatment with pegylated IFN-[alpha]2a and ribavirin for chronic hepatitis C virus infection (2006) J Infect Dis 194: 895–903.
Sarasin-Filipowicz M, Oakeley EJ, Duong FH et al Interferon signaling and treatment outcome in chronic hepatitis C (2008) Proc Natl Acad Sci U S A 105: 7034–7039.
Seth RB, Sun L, Ea CK et al Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kB and IRF3 (2005) Cell 122: 669–682.
Shimakami T, Lanford RE, Lemon SM Hepatitis C: recent successes and continuing challenges in the development of improved treatment modalities (2009) Curr Opin Pharmacol 9: 537–544.
Shoukry NH, Grakoui A, Houghton M et al Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection (2003) J Exp Med 197: 1645–1655.
Su AI, Pezacki JP, Wodicka L et al Genomic analysis of the host reponse to hepatitis C virus infection (2002) Proc Natl Acad Sci U S A 99: 15669–15674.
Suppiah V, Moldovan M, Ahlenstiel G et al IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy (2009) Nat Genet 41: 1100–1104.
Tanaka Y, Nishida N, Sugiyama M et al Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C (2009) Nat Genet 41: 1105–1109.
Thimme R, Oldach D, Chang KM et al Determinants of viral clearance and persistence during acute hepatitis C virus infection (2001) J Exp Med 194: 1395–1406.
Thomas DL, Astemborski J, Rai RM et al The natural history of hepatitis C virus infection - Host, viral, and environmental factors (2000) JAMA 284: 450–456.
Thomas DL, Thio CL, Martin MP et al Genetic variation in IL28B and spontaneous clearance of hepatitis C virus (2009) Nature 461: 798–801.
Urbani S, Amadei B, Tola D et al PD-1 expression in acute hepatitis C is associated with HCV-specific CD8 exhaustion (2006) J Virol 80: 11398–11403.
Weiner A, Erickson AL, Kansopon J et al Persistent hepatitis C virus infection in a chimpanzee is associated with emergence of a cytotoxic T lymphocyte escape variant (1995) Proc Natl Acad Sci U S A 92: 2755–2759.
Xu LG, Wang YY, Han KJ et al VISA is an adapter protein required for virus-triggered IFN-beta signaling (2005) Mol Cell 19: 727–740.
Zhu H, Butera M, Nelson DR et al Novel type I interferon IL-28A suppresses hepatitis C viral RNA replication (2005) Virol J 2: 80.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2011 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Lanford, R.E. (2011). Innate Signatures of Immune Mediated Resolution and Persistence of Hepatitis C Virus Infections. In: Marincola, F., Wang, E. (eds) Immunologic Signatures of Rejection. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-7219-4_9
Download citation
DOI: https://doi.org/10.1007/978-1-4419-7219-4_9
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4419-7218-7
Online ISBN: 978-1-4419-7219-4
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)