Rous-Whipple Award Lecture. Viruses, immunity, and cancer: lessons from hepatitis B.

The host-virus interactions that determine the outcome of viral infections have fascinated me ever since medical school. My first opportunity to actively pursue this interest came when I was lucky enough to be part of a team at the National Institutes of Health that transmitted the hepatitis B virus (HBV) to chimpanzees. 1 Thus began a longstanding interest in the immunobiology of persistent human viral infections, especially those that infect the liver. I am greatly honored that this work has been recognized by the Rous-Whipple Award this year, giving me this opportunity to describe our current state of understanding of these infections.

[1]  L. Gooding.  Virus proteins that counteract host immune defenses , 1992, Cell.

[2]  K. Hertogs,et al.  Endonexin II, present on human liver plasma membranes, is a specific binding protein of small hepatitis B virus (HBV) envelope protein. , 1993, Virology.

[3]  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.

[4]  F. Chisari,et al.  Hepatitis B virus structure and biology. , 1989, Microbial pathogenesis.

[5]  F. Schödel,et al.  Characterization of self‐reactive T cells that evade tolerance in hepatitis B e antigen transgenic mice , 1995, European journal of immunology.

[6]  A Sette,et al.  Human class I supertypes and CTL repertoires extend to chimpanzees. , 1998, Journal of immunology.

[7]  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.

[8]  J. Hoofnagle,et al.  Peroxidase‐anti‐peroxidase detection of hepatitis B surface and core antigen in liver biopsy specimens from patients with chronic type B hepatitis , 1987, Journal of medical virology.

[9]  F. Chisari,et al.  Noncytopathic Clearance of Lymphocytic Choriomeningitis Virus from the Hepatocyte , 1999, The Journal of experimental medicine.

[10]  H. Varmus,et al.  The molecular biology of the hepatitis B viruses. , 1987, Annual review of biochemistry.

[11]  F. Chisari,et al.  La Autoantigen Specifically Recognizes a Predicted Stem-Loop in Hepatitis B Virus RNA , 1999, Journal of Virology.

[12]  A. Sette,et al.  Natural variants of cytotoxic epitopes are T-cell receptor antagonists for antiviral cytotoxic T cells , 1994, Nature.

[13]  J. Taylor,et al.  Asymmetric replication of duck hepatitis B virus DNA in liver cells: Free minus-strand DNA. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[14]  A. Alcamí,et al.  Cytokine receptors encoded by poxviruses: a lesson in cytokine biology. , 1995, Immunology today.

[15]  K. Sutherland,et al.  Hepatitis B virus surface antigen binds to apolipoprotein H , 1994, Journal of virology.

[16]  R. Palmiter,et al.  Expression of hepatitis B virus large envelope polypeptide inhibits hepatitis B surface antigen secretion in transgenic mice , 1986, Journal of virology.

[17]  J. Summers,et al.  Mapping of the cohesive overlap of duck hepatitis B virus DNA and of the site of initiation of reverse transcription , 1984, Journal of virology.

[18]  F. Chisari,et al.  Cytotoxic T lymphocytes inhibit hepatitis B virus gene expression by a noncytolytic mechanism in transgenic mice. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[19]  F. Chisari,et al.  Hepatitis B virus persistence after recovery from acute viral hepatitis. , 1994, The Journal of clinical investigation.

[20]  P. Simmonds.  Variability of hepatitis C virus , 1995, Hepatology.

[21]  J. Carlson,et al.  Risk of cirrhosis and primary liver cancer in alpha 1-antitrypsin deficiency. , 1986, The New England journal of medicine.

[22]  J. Hoofnagle,et al.  Acute type A hepatitis during chronic hepatitis B virus infection: Association of depressed hepatitis B virus replication with appearance of endogenous alpha interferon , 1984, Journal of medical virology.

[23]  F. Chisari,et al.  Interleukin-2 downregulates hepatitis B virus gene expression in transgenic mice by a posttranscriptional mechanism. , 1993, Journal of virology.

[24]  F. Chisari,et al.  Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes. , 1996, Immunity.

[25]  G. Natoli,et al.  Hepatitis B virus X gene product acts as a transactivator in vivo. , 1994, Journal of hepatology.

[26]  C. Peschle,et al.  Transferrin receptor mediates uptake and presentation of hepatitis B envelope antigen by T lymphocytes , 1992, The Journal of experimental medicine.

[27]  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.

[28]  A. Perelson,et al.  Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection , 1995, Nature.

[29]  F. Chisari,et al.  Strong, sustained hepatocellular proliferation precedes hepatocarcinogenesis in hepatitis B surface antigen transgenic mice , 1995, Hepatology.

[30]  F. Chisari,et al.  Hepatitis B virus nucleocapsid particles do not cross the hepatocyte nuclear membrane in transgenic mice , 1994, Journal of virology.

[31]  V. Pasquetto,et al.  Pathogenetic effector function of CD4-positive T helper 1 cells in hepatitis B virus transgenic mice. , 1997, Journal of immunology.

[32]  F. Chisari,et al.  Tumor necrosis factor alpha negatively regulates hepatitis B virus gene expression in transgenic mice , 1992, Journal of virology.

[33]  F. Zoulim,et al.  Woodchuck hepatitis virus X protein is required for viral infection in vivo , 1994, Journal of virology.

[34]  F. Chisari,et al.  The hepatitis B virus (HBV) precore protein inhibits HBV replication in transgenic mice , 1996, Journal of virology.

[35]  M. Mondelli,et al.  Significance of the immune response to a major, conformational B-cell epitope on the hepatitis C virus NS3 region defined by a human monoclonal antibody , 1994, Journal of virology.

[36]  F. Chisari,et al.  Immune Pathogenesis of Hepatocellular Carcinoma , 1998, The Journal of experimental medicine.

[37]  A. Sonnenberg,et al.  Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. , 1985, The New England journal of medicine.

[38]  F. Chisari,et al.  Class I-restricted cytotoxic T lymphocytes are directly cytopathic for their target cells in vivo. , 1994, Journal of immunology.

[39]  J. Wands,et al.  Posttranscriptional regulation of hepatitis B virus replication by the precore protein , 1997, Journal of virology.

[40]  A. Hughes,et al.  Persistent hepatitis C virus infection in a chimpanzee is associated with emergence of a cytotoxic T lymphocyte escape variant. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[41]  A. Sette,et al.  A single TCR antagonist peptide inhibits experimental allergic encephalomyelitis mediated by a diverse T cell repertoire. , 1994, Journal of immunology.

[42]  F. Chisari,et al.  Interleukin-2 and alpha/beta interferon down-regulate hepatitis B virus gene expression in vivo by tumor necrosis factor-dependent and -independent pathways , 1994, Journal of virology.

[43]  F. Chisari,et al.  Breaking tolerance leads to autoantibody production but not autoimmune liver disease in hepatitis B virus envelope transgenic mice. , 1995, Journal of immunology.

[44]  F. Chisari,et al.  High-level hepatitis B virus replication in transgenic mice , 1995, Journal of virology.

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

[46]  F. Chisari,et al.  Viral cross talk: intracellular inactivation of the hepatitis B virus during an unrelated viral infection of the liver. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[47]  C. Harris,et al.  Hepatitis B virus X protein inhibits p53 sequence-specific DNA binding, transcriptional activity, and association with transcription factor ERCC3. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[48]  P. Galle,et al.  Involvement of the CD95 (APO-1/Fas) receptor and ligand in liver damage , 1995, The Journal of experimental medicine.

[49]  D J Moss,et al.  Dominant selection of an invariant T cell antigen receptor in response to persistent infection by Epstein-Barr virus , 1994, The Journal of experimental medicine.

[50]  T. Friedmann.  Molecular Genetic Medicine , 1991 .

[51]  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.

[52]  J. Summers,et al.  Replication of the genome of a hepatitis B-like virus by reverse transcription of an RNA intermediate , 1982, Cell.

[53]  R. Palmiter,et al.  A transgenic mouse model of the chronic hepatitis B surface antigen carrier state. , 1985, Science.

[54]  K. Koike,et al.  High‐level expression of hepatitis B virus HBx gene and hepatocarcinogenesis in transgenic mice , 1994, Hepatology.

[55]  R. Sprengel,et al.  Replication strategy of human hepatitis B virus , 1987, Journal of virology.

[56]  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.

[57]  F. Chisari,et al.  Posttranscriptional clearance of hepatitis B virus RNA by cytotoxic T lymphocyte-activated hepatocytes. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[58]  P. Hofschneider,et al.  The hepatitis B virus large surface protein (LHBs) is a transcriptional activator. , 1996, Virology.

[59]  J. Carlson,et al.  Chronic 'cryptogenic' liver disease and malignant hepatoma in intermediate alpha 1-antitrypsin deficiency identified by a Pi Z-specific monoclonal antibody. , 1985, Scandinavian journal of gastroenterology.

[60]  C. Chu,et al.  Role of hepatitis C and delta viruses in the termination of chronic hepatitis B surface antigen carrier state: a multivariate analysis in a longitudinal follow-up study. , 1994, The Journal of infectious diseases.

[61]  B. Walker,et al.  Longitudinal analysis of T cell receptor (TCR) gene usage by human immunodeficiency virus 1 envelope-specific cytotoxic T lymphocyte clones reveals a limited TCR repertoire , 1994, The Journal of experimental medicine.

[62]  F. Chisari,et al.  Interleukin-12 inhibits hepatitis B virus replication in transgenic mice , 1997, Journal of virology.

[63]  F. Chisari,et al.  Inhibition of Hepatitis B Virus Replication during Adenovirus and Cytomegalovirus Infections in Transgenic Mice , 1998, Journal of Virology.

[64]  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.

[65]  F. Chisari.  Hepatitis B virus biology and pathogenesis. , 1992, Molecular genetic medicine.

[66]  R. Miller,et al.  Hepatitis B viral DNA-RNA hybrid molecules in particles from infected liver are converted to viral DNA molecules during an endogenous DNA polymerase reaction. , 1984, Virology.

[67]  R. Palmiter,et al.  Molecular pathogenesis of hepatocellular carcinoma in hepatitis B virus transgenic mice , 1989, Cell.

[68]  J. Summers,et al.  Formation of the pool of covalently closed circular viral DNA in hepadnavirus-infected cells , 1986, Cell.

[69]  W. Rutter,et al.  Assembly of viral particles in Xenopus oocytes: pre-surface-antigens regulate secretion of the hepatitis B viral surface envelope particle. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[70]  M. Houghton,et al.  Hepatitis C virus: the major causative agent of viral non-A, non-B hepatitis. , 1990, British medical bulletin.

[71]  F. Chisari,et al.  Hepatitis B Virus RNA-Binding Proteins Associated with Cytokine-Induced Clearance of Viral RNA from the Liver of Transgenic Mice , 1999, Journal of Virology.

[72]  F. Chisari,et al.  Hepatocarcinogenesis due to chronic liver cell injury in hepatitis B virus transgenic mice. , 1990, Cancer research.

[73]  D. Green,et al.  Fas Ligand-Induced Apoptosis as a Mechanism of Immune Privilege , 1995, Science.

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

[75]  P. Hofschneider,et al.  Hepatitis B virus transactivator HBx uses a tumour promoter signalling pathway , 1993, Nature.

[76]  P. Marion,et al.  Hepadnaviruses and retroviruses share genome homology and features of replication , 1987, Hepatology.

[77]  F. Chisari,et al.  Multiple oncogenes and tumor suppressor genes are structurally and functionally intact during hepatocarcinogenesis in hepatitis B virus transgenic mice. , 1992, Cancer research.

[78]  F. Chisari,et al.  Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis , 1993, The Journal of experimental medicine.

[79]  R. Palmiter,et al.  Structural and pathological effects of synthesis of hepatitis B virus large envelope polypeptide in transgenic mice. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[80]  J. Hoofnagle,et al.  Viral hepatitis and liver disease , 1984 .

[81]  J. Altman,et al.  Persistence of memory CD8 T cells in MHC class I-deficient mice. , 1999, Science.

[82]  Lu-Yu Hwang,et al.  HEPATOCELLULAR CARCINOMA AND HEPATITIS B VIRUS A Prospective Study of 22 707 Men in Taiwan , 1981, The Lancet.

[83]  H. Varmus,et al.  Biochemical and genetic evidence for the hepatitis B virus replication strategy. , 1986, Science.

[84]  N. Shastri.  Antigen processing and recognition Edited by James McCluskey. Boca Raton: CRC Press. (1991). 257 pp. $139.95 , 1992, Cell.

[85]  B. Ames,et al.  Extensive oxidative DNA damage in hepatocytes of transgenic mice with chronic active hepatitis destined to develop hepatocellular carcinoma. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[86]  B. Walker,et al.  Hepatitis C virus (HCV)-specific cytotoxic T lymphocytes recognize epitopes in the core and envelope proteins of HCV , 1993, Journal of virology.

[87]  T. Tokino,et al.  Integration of hepatitis B virus DNA and its implications for hepatocarcinogenesis. , 1990, Molecular biology & medicine.

[88]  G. Natoli,et al.  Induction of the DNA-binding activity of c-jun/c-fos heterodimers by the hepatitis B virus transactivator pX , 1994, Molecular and cellular biology.

[89]  A. Siddiqui,et al.  HBV X protein alters the DNA binding specificity of CREB and ATF-2 by protein-protein interactions , 1991, Science.

[90]  W. Mason,et al.  Evidence that a capped oligoribonucleotide is the primer for duck hepatitis B virus plus-strand DNA synthesis , 1986, Journal of virology.

[91]  R. Palmiter,et al.  Immunobiology and pathogenesis of hepatocellular injury in hepatitis B virus transgenic mice. , 1990, Science.

[92]  Y. Suzuki,et al.  The effect of anti-IFN-gamma antibody on the protective effect of Lyt-2+ immune T cells against toxoplasmosis in mice. , 1990, Journal of immunology.

[93]  Y. Miyakawa,et al.  A hepatitis B surface antigen polypeptide (P31) with the receptor for polymerized human as well as chimpanzee albumins. , 1983, Gastroenterology.

[94]  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.

[95]  Persephone Borrow,et al.  Major expansion of CD8+ T cells with a predominant Vβ usage during the primary immune response to HIV , 1994, Nature.

[96]  B. Woda,et al.  Lymphocyte apoptosis during the silencing of the immune response to acute viral infections in normal, lpr, and Bcl-2-transgenic mice. , 1995, The American journal of pathology.

[97]  H. Zentgraf,et al.  Precore-mediated inhibition of hepatitis B virus progeny DNA synthesis , 1993, Journal of virology.

[98]  B. Portmann,et al.  Hepatocellular carcinoma in the non-cirrhotic liver: a comparison with that complicating cirrhosis. , 1984, The Quarterly journal of medicine.

[99]  Xiping Wei,et al.  Antiviral pressure exerted by HIV-l-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus , 1997, Nature Medicine.

[100]  B. Walker,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. , 1995, The Journal of clinical investigation.

[101]  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.

[102]  M. Gerber,et al.  Cytoplasmic hepatitis B antigen in "ground-glass" hepatocytes of carriers. , 1973, Archives of pathology.

[103]  J. Wands,et al.  Carboxypeptidase D Is an Avian Hepatitis B Virus Receptor , 1999, Journal of Virology.

[104]  W. Caselmann,et al.  Hepatitis B virus transactivator MHBst: activation of NF‐kappa B, selective inhibition by antioxidants and integral membrane localization. , 1992, The EMBO journal.

[105]  G. Jay,et al.  HBx gene of hepatitis B virus induces liver cancer in transgenic mice , 1991, Nature.

[106]  F. Chisari,et al.  Transmission of type B viral hepatitis to chimpanzees. , 1973, The Journal of infectious diseases.

[107]  P. Klenerman,et al.  Persistence of lymphocytic choriomeningitis virus at very low levels in immune mice. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[108]  W. Fleig,et al.  Hepatocellular carcinoma in type I glycogen storage disease , 1988, Hepatology.

[109]  M. Rehli,et al.  Identification of a membrane-bound carboxypeptidase as the mammalian homolog of duck gp180, a hepatitis B virus-binding protein. , 1997, Life sciences.