The immune response during hepatitis B virus infection.

Hepatitis B virus (HBV) is a major cause of chronic liver inflammation worldwide. Recent knowledge of the virological and immunological events secondary to HBV infection has increased our understanding of the mechanisms involved in viral clearance and persistence. In this review, how the early virological and immunological events might influence the development of a coordinate activation of adaptive immunity necessary to control HBV infection is analysed. The mechanism(s) by which high levels of viral antigens, liver immunological features, regulatory cells and dendritic cell defects might maintain the HBV-specific immunological collapse, typical of chronic hepatitis B patients, is also examined.

[1]  S. Sakaguchi Regulatory T cells , 2000, Cell.

[2]  I. Klein,et al.  Complete differentiation of CD8+ T cells activated locally within the transplanted liver , 2006, The Journal of experimental medicine.

[3]  Roger Williams,et al.  Lamivudine plus interleukin‐12 combination therapy in chronic hepatitis B: Antiviral and immunological activity , 2005, Hepatology.

[4]  L. Moretta,et al.  Human natural killer cells: Molecular mechanisms controlling NK cell activation and tumor cell lysis. , 2005, Immunology letters.

[5]  F. Chisari,et al.  Stealth and Cunning: Hepatitis B and Hepatitis C Viruses , 2005, Journal of Virology.

[6]  F. Chisari,et al.  Oscillating CD8(+) T cell effector functions after antigen recognition in the liver. , 2005, Immunity.

[7]  E. Kuipers,et al.  Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection , 2005, Hepatology.

[8]  G. Missale,et al.  Acute phase HBV‐specific T cell responses associated with HBV persistence after HBV/HCV coinfection , 2005, Hepatology.

[9]  F. Chisari,et al.  Immune Tolerance Split between Hepatitis B Virus Precore and Core Proteins , 2005, Journal of Virology.

[10]  S. Lewin,et al.  Reduced Hepatitis B Virus (HBV)-Specific CD4+ T-Cell Responses in Human Immunodeficiency Virus Type 1-HBV-Coinfected Individuals Receiving HBV-Active Antiretroviral Therapy , 2005, Journal of Virology.

[11]  F. Chisari,et al.  A function of the hepatitis B virus precore protein is to regulate the immune response to the core antigen. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[12]  P. Galle,et al.  Phenotype and function of monocyte derived dendritic cells in chronic hepatitis B virus infection. , 2004, The Journal of general virology.

[13]  J. Kwekkeboom,et al.  Functional impairment of myeloid and plasmacytoid dendritic cells of patients with chronic hepatitis B , 2004, Hepatology.

[14]  G. McCaughan,et al.  The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity. , 2004, The Journal of clinical investigation.

[15]  Geoffrey Dusheiko,et al.  Longitudinal Analysis of CD8+ T Cells Specific for Structural and Nonstructural Hepatitis B Virus Proteins in Patients with Chronic Hepatitis B: Implications for Immunotherapy , 2004, Journal of Virology.

[16]  Graeme E Price,et al.  Differential Tissue-Specific Regulation of Antiviral CD8+ T-Cell Immune Responses during Chronic Viral Infection , 2004, Journal of Virology.

[17]  D. Accapezzato,et al.  Hepatic expansion of a virus-specific regulatory CD8+ T cell population in chronic hepatitis C virus infection , 2004 .

[18]  D. Ganem,et al.  Hepatitis B virus infection--natural history and clinical consequences. , 2004, The New England journal of medicine.

[19]  S. Akira,et al.  Species-Specific Recognition of Single-Stranded RNA via Toll-like Receptor 7 and 8 , 2004, Science.

[20]  M. Imawari,et al.  Hepatitis B core antigen stimulates interleukin‐10 secretion by both T cells and monocytes from peripheral blood of patients with chronic hepatitis B virus infection , 2004, Clinical and experimental immunology.

[21]  Roy M. Anderson,et al.  Underwhelming the Immune Response: Effect of Slow Virus Growth on CD8+-T-Lymphocyte Responses , 2004, Journal of Virology.

[22]  J. Goedert,et al.  Comprehensive Analysis of Class I and Class II HLA Antigens and Chronic Hepatitis B Virus Infection , 2003, Journal of Virology.

[23]  D. Milich,et al.  Exploring the biological basis of hepatitis B e antigen in hepatitis B virus infection , 2003, Hepatology.

[24]  A. Bertoletti,et al.  Transient restoration of anti-viral T cell responses induced by lamivudine therapy in chronic hepatitis B. , 2003, Journal of hepatology.

[25]  B. Rouse,et al.  CD4+CD25+ T Cells Regulate Virus-specific Primary and Memory CD8+ T Cell Responses , 2003, The Journal of experimental medicine.

[26]  Antonio Bertoletti,et al.  Kinetics of the immune response during HBV and HCV infection , 2003, Hepatology.

[27]  E. Wherry,et al.  Viral Persistence Alters CD8 T-Cell Immunodominance and Tissue Distribution and Results in Distinct Stages of Functional Impairment , 2003, Journal of Virology.

[28]  R. Purcell,et al.  CD8+ T Cells Mediate Viral Clearance and Disease Pathogenesis during Acute Hepatitis B Virus Infection , 2003, Journal of Virology.

[29]  Jung-min Park,et al.  HLA-A2 1 restricted peptides from the HBx antigen induce specific CTL responses in vitro and in vivo. , 2002, Vaccine.

[30]  S. Rose-John,et al.  Reduced virus specific T helper cell induction by autologous dendritic cells in patients with chronic hepatitis B – restoration by exogenous interleukin‐12 , 2002, Clinical and experimental immunology.

[31]  A. Sette,et al.  Immunogenicity and Tolerogenicity of Hepatitis B Virus Structural and Nonstructural Proteins: Implications for Immunotherapy of Persistent Viral Infections , 2002, Journal of Virology.

[32]  D. Stolz,et al.  Reduction in the circulating pDC1/pDC2 ratio and impaired function of ex vivo-generated DC1 in chronic hepatitis B infection. , 2002, Clinical immunology.

[33]  R. Locksley,et al.  Activation of a nonclassical NKT cell subset in a transgenic mouse model of hepatitis B virus infection. , 2002, Immunity.

[34]  B. Tennant,et al.  Deficiencies in the Acute-Phase Cell-Mediated Immune Response to Viral Antigens Are Associated with Development of Chronic Woodchuck Hepatitis Virus Infection following Neonatal Inoculation , 2002, Journal of Virology.

[35]  F. Chisari,et al.  Cutting Edge: Inhibition of Hepatitis B Virus Replication by Activated NK T Cells Does Not Require Inflammatory Cell Recruitment to the Liver1 , 2001, The Journal of Immunology.

[36]  B. McMahon,et al.  Chronic hepatitis B , 2001, Hepatology.

[37]  Tomasz P. Michalak,et al.  Augmented hepatic interferon gamma expression and T‐cell influx characterize acute hepatitis progressing to recovery and residual lifelong virus persistence in experimental adult woodchuck hepatitis virus infection , 2001, Hepatology.

[38]  R. Flavell,et al.  Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3 , 2001, Nature.

[39]  D. Moskophidis,et al.  Critical Role for Alpha/Beta and Gamma Interferons in Persistence of Lymphocytic Choriomeningitis Virus by Clonal Exhaustion of Cytotoxic T Cells , 2001, Journal of Virology.

[40]  F. Powrie,et al.  Regulatory T cells in the control of immune pathology , 2001, Nature Immunology.

[41]  Hui-fen Wang,et al.  Dysfunction of peripheral blood dendritic cells from patients with chronic hepatitis B virus infection. , 2001, World journal of gastroenterology.

[42]  D. Thiele,et al.  Virally Infected Hepatocytes Are Resistant to Perforin-Dependent CTL Effector Mechanisms1 , 2001, The Journal of Immunology.

[43]  R. Lanford,et al.  DNA Microarray Analysis of Chimpanzee Liver during Acute Resolving Hepatitis C Virus Infection , 2001, Journal of Virology.

[44]  F. Leithäuser,et al.  Activating Immunity in the Liver. I. Liver Dendritic Cells (but Not Hepatocytes) Are Potent Activators of IFN-γ Release by Liver NKT Cells1 , 2001, The Journal of Immunology.

[45]  H. Tsubouchi,et al.  Identification of hepatitis B virus-specific CTL epitopes presented by HLA-A*2402, the most common HLA class I allele in East Asia. , 2001, Journal of hepatology.

[46]  C. Biron Interferons α and β as Immune Regulators—A New Look , 2001 .

[47]  B. Fazekas de St. Groth,et al.  Antigen-Specific Primary Activation of CD8+ T Cells Within the Liver1 , 2001, The Journal of Immunology.

[48]  A. Sette,et al.  Degenerate Immunogenicity of an HLA-A2-Restricted Hepatitis B Virus Nucleocapsid Cytotoxic T-Lymphocyte Epitope That Is Also Presented by HLA-B51 , 2001, Journal of Virology.

[49]  G. Ogg,et al.  Lamivudine treatment can overcome cytotoxic T‐cell hyporesponsiveness in chronic hepatitis B: New perspectives for immune therapy , 2001, Hepatology.

[50]  T. Michalak,et al.  In Vitro and In Vivo Infectivity and Pathogenicity of the Lymphoid Cell-Derived Woodchuck Hepatitis Virus , 2001, Journal of Virology.

[51]  P. Klenerman,et al.  Impairment of Cd4+ T Cell Responses during Chronic Virus Infection Prevents Neutralizing Antibody Responses against Virus Escape Mutants , 2001, The Journal of experimental medicine.

[52]  B. Tennant,et al.  Pathogenesis of experimental neonatal woodchuck hepatitis virus infection: Chronicity as an outcome of infection is associated with a diminished acute hepatitis that is temporally deficient for the expression of interferon gamma and tumor necrosis factor‐alpha messenger RNAs , 2001, Hepatology.

[53]  D. Vergani,et al.  Incubation phase of acute hepatitis B in man: Dynamic of cellular immune mechanisms , 2000, Hepatology.

[54]  F. Chisari,et al.  Natural Killer T Cell Activation Inhibits Hepatitis B Virus Replication in Vivo , 2000, The Journal of experimental medicine.

[55]  Alan S. Perelson,et al.  Kinetics of Acute Hepatitis B Virus Infection in Humans , 2000, The Journal of experimental medicine.

[56]  B. Tennant,et al.  Temporal pathogenesis of experimental neonatal woodchuck hepatitis virus infection: Increased initial viral load and decreased severity of acute hepatitis during the development of chronic viral infection , 2000, Hepatology.

[57]  F. Chisari,et al.  Intrahepatic Induction of Alpha/Beta Interferon Eliminates Viral RNA-Containing Capsids in Hepatitis B Virus Transgenic Mice , 2000, Journal of Virology.

[58]  Antonio Bertoletti,et al.  The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection. , 2000 .

[59]  D. Metz,et al.  The liver as a site of T‐cell apoptosis: graveyard, or killing field? , 2000, Immunological reviews.

[60]  F. Chisari,et al.  Relative Sensitivity of Hepatitis B Virus and Other Hepatotropic Viruses to the Antiviral Effects of Cytokines , 2000, Journal of Virology.

[61]  C. Seeger,et al.  Hepatitis B Virus Biology , 2000, Microbiology and Molecular Biology Reviews.

[62]  D. Vergani,et al.  The Role of Virus-Specific Cd8+ Cells in Liver Damage and Viral Control during Persistent Hepatitis B Virus Infection , 2000, The Journal of experimental medicine.

[63]  D. Vergani,et al.  Direct ex vivo analysis of hepatitis B virus-specific CD8(+) T cells associated with the control of infection. , 1999, Gastroenterology.

[64]  B. Hartmann,et al.  Virus-specific lymphokine production differs quantitatively but not qualitatively in acute and chronic hepatitis B infection. , 1999, Virology.

[65]  Tomasz P. Michalak,et al.  Persistence of infectious hepadnavirus in the offspring of woodchuck mothers recovered from viral hepatitis. , 1999, The Journal of clinical investigation.

[66]  M. Shapiro,et al.  Viral clearance without destruction of infected cells during acute HBV infection. , 1999, Science.

[67]  K. Meyer zum Büschenfelde,et al.  Kinetics of hepatitis B surface antigen–specific immune responses in acute and chronic hepatitis B or After HBs vaccination: Stimulation of the in vitro antibody response by interferon gamma , 1999, Hepatology.

[68]  Spyros A. Kalams,et al.  The Critical Need for CD4 Help in Maintaining Effective Cytotoxic T Lymphocyte Responses , 1998, The Journal of experimental medicine.

[69]  H. Rammensee,et al.  Protective Immunity Does Not Correlate with the Hierarchy of  Virus-specific Cytotoxic T Cell Responses to Naturally Processed Peptides , 1998, The Journal of experimental medicine.

[70]  M. Chen,et al.  The secreted hepatitis B precore antigen can modulate the immune response to the nucleocapsid: a mechanism for persistence. , 1998, Journal of immunology.

[71]  C. Rabourdin-Combe,et al.  Hepatocytes induce functional activation of naive CD8+ T lymphocytes but fail to promote survival , 1998, European journal of immunology.

[72]  L. Seeff,et al.  Natural history of hepatitis C , 1997, Hepatology.

[73]  G. Ferrara,et al.  Molecular features of the hepatitis B virus nucleocapsid T‐cell epitope 18‐27: Interaction with HLA and T‐cell receptor , 1997, Hepatology.

[74]  H. Thomas,et al.  Heterozygote advantage for HLA class-II type in hepatitis B virus infection , 1997, Nature Genetics.

[75]  J. Sidney,et al.  Human histocompatibility leukocyte antigen-binding supermotifs predict broadly cross-reactive cytotoxic T lymphocyte responses in patients with acute hepatitis. , 1997, The Journal of clinical investigation.

[76]  R. Williams,et al.  Interleukin-12 induction of Th1 cytokines is important for viral clearance in chronic hepatitis B. , 1997, The Journal of clinical investigation.

[77]  A. Bertoletti,et al.  Predominant T‐helper 1 cytokine profile of hepatitis B virus nucleocapsid‐specific T cells in acute self‐limited hepatitis B , 1997, Hepatology.

[78]  F. Chisari,et al.  The hepatitis B virus persists for decades after patients' recovery from acute viral hepatitis despite active maintenance of a cytotoxic T–lymphocyte response , 1996, Nature Medicine.

[79]  F. Chisari,et al.  Long-lasting memory T cell responses following self-limited acute hepatitis B. , 1996, The Journal of clinical investigation.

[80]  F. Chisari,et al.  To kill or to cure: options in host defense against viral infection. , 1996, Current opinion in immunology.

[81]  F. Chisari,et al.  Cytotoxic T lymphocyte responsiveness after resolution of chronic hepatitis B virus infection. , 1996, The Journal of clinical investigation.

[82]  F. Chisari,et al.  Hepatitis B virus (HBV) sequence variation of cytotoxic T lymphocyte epitopes is not common in patients with chronic HBV infection. , 1995, The Journal of clinical investigation.

[83]  B. Moss,et al.  The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis , 1995, The Journal of experimental medicine.

[84]  J. Cullen,et al.  Woodchuck hepatitis virus infections: very rapid recovery after a prolonged viremia and infection of virtually every hepatocyte , 1994, Journal of virology.

[85]  A. Sette,et al.  Cytotoxic T lymphocyte response to a wild type hepatitis B virus epitope in patients chronically infected by variant viruses carrying substitutions within the epitope , 1994, The Journal of experimental medicine.

[86]  J. Hoofnagle,et al.  High levels of viral replication during acute hepatitis B infection predict progression to chronicity , 1994, Journal of medical virology.

[87]  A. Vitiello,et al.  HLA A2 restricted cytotoxic T lymphocyte responses to multiple hepatitis B surface antigen epitopes during hepatitis B virus infection. , 1993, Journal of immunology.

[88]  F. Chisari,et al.  HLA-A31- and HLA-Aw68-restricted cytotoxic T cell responses to a single hepatitis B virus nucleocapsid epitope during acute viral hepatitis , 1993, The Journal of experimental medicine.

[89]  T. Wu,et al.  Rapid resolution of duck hepatitis B virus infections occurs after massive hepatocellular involvement , 1992, Journal of virology.

[90]  F. Chisari,et al.  HLA class I-restricted human cytotoxic T cells recognize endogenously synthesized hepatitis B virus nucleocapsid antigen. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[91]  F. Chisari,et al.  Cytotoxic T lymphocytes recognize an HLA-A2-restricted epitope within the hepatitis B virus nucleocapsid antigen , 1991, The Journal of experimental medicine.

[92]  U. Spengler,et al.  Hepatitis B virus antigen-specific T-cell activation in patients with acute and chronic hepatitis B. , 1991, Journal of hepatology.

[93]  F. Chisari,et al.  Identification of immunodominant T cell epitopes of the hepatitis B virus nucleocapsid antigen. , 1991, The Journal of clinical investigation.

[94]  H. Will,et al.  Wild-type and e antigen-minus hepatitis B viruses and course of chronic hepatitis. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[95]  A Valli,et al.  Cellular immune response to hepatitis B virus-encoded antigens in acute and chronic hepatitis B virus infection. , 1990, Journal of immunology.

[96]  J. Price,et al.  Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero? , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[97]  A. Bertoletti,et al.  The preS1 antigen of hepatitis B virus is highly immunogenic at the T cell level in man. , 1989, The Journal of clinical investigation.

[98]  R. Purcell,et al.  Natural history of woodchuck hepatitis virus infections during the course of experimental viral infection: molecular virologic features of the liver and lymphoid tissues , 1989, Journal of virology.

[99]  S. Iwarson,et al.  Successful postexposure vaccination against hepatitis B in chimpanzees , 1988, Journal of medical virology.

[100]  L. Otvos,et al.  Recognition of hepatitis B surface antigen by human T lymphocytes. Proliferative and cytotoxic responses to a major antigenic determinant defined by synthetic peptides. , 1988, Journal of immunology.

[101]  J. Senior,et al.  Hepatitis B immune globulin for accidental exposures among medical personnel: final report of a multicenter controlled trial. , 1978, The Journal of infectious diseases.

[102]  A. Alberti,et al.  Detection of a new antibody system reacting with Dane particles in hepatitis B virus infection. , 1978, British medical journal.

[103]  R. Purcell,et al.  Hepatitis B antigens in serum and liver of chimpanzees acutely infected with hepatitis B virus , 1975, Infection and immunity.

[104]  O. Box Functional impairment of myeloid and plasmacytoid dendritic cells of pat ients with chronic hepatitis B , 2005 .

[105]  Roger Williams,et al.  Modulation of the CD8 -T-Cell Response by CD4 CD25 Regulatory T Cells in Patients with Hepatitis B Virus Infection , 2005 .

[106]  R. Purcell,et al.  Genomic analysis of the host response to hepatitis B virus infection. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[107]  D. Accapezzato,et al.  Hepatic expansion of a virus-specific regulatory CD8(+) T cell population in chronic hepatitis C virus infection. , 2004, The Journal of clinical investigation.

[108]  M. Morimoto,et al.  The role of hepatitis B virus-specific memory CD8 T cells in the control of viral replication. , 2002, Journal of hepatology.

[109]  A. King,et al.  Escaping High Viral Load Exhaustion: CD8 Cells with Altered Tetramer Binding in Chronic Hepatitis B Virus Infection , 2002 .

[110]  R. Thimme Inaugural Article: Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease , 2002 .

[111]  R. Purcell,et al.  CD 8 T Cells Mediate Viral Clearance and Disease Pathogenesis during Acute Hepatitis B Virus Infection † , 2002 .

[112]  C. Biron Interferons alpha and beta as immune regulators--a new look. , 2001, Immunity.

[113]  F. Chisari,et al.  Noncytolytic control of viral infections by the innate and adaptive immune response. , 2001, Annual review of immunology.

[114]  C Caux,et al.  Immunobiology of dendritic cells. , 2000, Annual review of immunology.

[115]  F. Chisari,et al.  Hepatitis B virus immunopathogenesis. , 1995, Annual review of immunology.

[116]  R. Figueroa Barrios [Chronic hepatitis]. , 1995, Revista de gastroenterologia del Peru : organo oficial de la Sociedad de Gastroenterologia del Peru.

[117]  F. Chisari,et al.  HLA-A31- and HLA-Aw68-restricted Cytotoxic T Cell Responses to a Single Hepatitis B Virus Nucleocapsid Epitope during Acute Viral Hepatitis By Gabriele Missale,* AUan Redeker,~ John Person,$ , 1993 .

[118]  J. Sung,et al.  Acute exacerbations of chronic type B hepatitis are accompanied by increased T cell responses to hepatitis B core and e antigens. Implications for hepatitis B e antigen seroconversion. , 1992, The Journal of clinical investigation.

[119]  R. W. Mccollum The natural history of hepatitis. , 1969, Bulletin of the New York Academy of Medicine.