title: Cellular immune responses to the hepatitis B virus polymerase.
abstract: CD4 T cells play an important role in hepatitis B virus (HBV) infection by secretion of Th1 cytokines that down-regulate HBV replication, and by promoting CD8 T cell and B cell responses. We have identified and characterized 10 CD4 T cell epitopes within polymerase and used them to analyze the immunological effects of long-term antiviral therapy as compared with spontaneous recovery from HBV infection. Candidate epitopes were tested for binding to 14 HLA-DR molecules and in IFN-gamma ELISPOT and cytotoxicity assays using peripheral blood lymphocytes from 66 HBV-infected patients and 16 uninfected controls. All 10 epitopes bound with high affinity to the most prevalent HLA-DR Ags, were conserved among HBV genomes, and induced IFN-gamma responses from HBV-specific CD4+ T cells. Several epitopes contained nested MHC class I motifs and stimulated HBV-specific IFN-gamma production and cytotoxicity of CD8+ T cells. HBV polymerase-specific responses were more frequent during acute, self-limited hepatitis and after recovery (12 of 18; 67%) than during chronic hepatitis (16 of 48 (33%); p=0.02). Antiviral therapy of chronic patients restored HBV polymerase and core-specific T cell responses during the first year of treatment, but thereafter, responses decreased and, after 3 years, were no more frequent than in untreated patients. Decreased T cell responsiveness during prolonged therapy was associated with increased prevalence of lamivudine-resistant HBV mutants and increased HBV titers. The data provide a rationale for the combination of antiviral and immunostimulatory therapy. These newly described HBV polymerase epitopes could be a valuable component of a therapeutic vaccine for a large and ethnically diverse patient population.
authors.affiliation: Liver Diseases Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
authors.forename: Eishiro
authors.initials: E
authors.lastname: Mizukoshi
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.forename: Brian
authors.initials: B
authors.lastname: Livingston
authors.forename: Marc
authors.initials: M
authors.lastname: Ghany
authors.forename: Jay H
authors.initials: JH
authors.lastname: Hoofnagle
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Barbara
authors.initials: B
authors.lastname: Rehermann
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000821:virology; D003429:Cross Reactions; D004797:Enzyme-Linked Immunosorbent Assay; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D015684:Gene Products, pol / Q000276:immunology* / Q000378:metabolism; D006684:HLA-DR Antigens / Q000378:metabolism; D006515:Hepatitis B virus / Q000201:enzymology* / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D006801:Humans; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000821:virology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D015684:Gene Products, pol; D006684:HLA-DR Antigens; C066027:P protein, Hepatitis B virus; D010446:Peptide Fragments; D007371:Interferon-gamma