title: Immune tolerance split between hepatitis B virus precore and core proteins.
abstract: The function of the hepatitis B virus (HBV) precore or HBeAg is largely unknown because it is not required for viral assembly, infection, or replication. However, the HBeAg does appear to play a role in viral persistence. It has been suggested that the HBeAg may promote HBV chronicity by functioning as an immunoregulatory protein. As a model of chronic HBeAg exposure and to examine the tolerogenic potential of the HBV precore and core (HBcAg) proteins, HBc/HBeAg-transgenic (Tg) mice crossed with T cell receptor (TCR)-Tg mice expressing receptors for the HBc/HBeAgs (i.e., TCR-antigen double-Tg pairs) were produced. This study revealed three phenotypes of HBe/HBcAg-specific T-cell tolerance: (i) profound T-cell tolerance most likely mediated by clonal deletion, (ii) T-cell clonal ignorance, and (iii) nondeletional T-cell tolerance mediated by clonal anergy and dependent on the structure, location, and concentration of the tolerogen. The secreted HBeAg is significantly more efficient than the intracellular HBcAg at eliciting T-cell tolerance. The split T-cell tolerance between the HBeAg and the HBcAg and the clonal heterogeneity of HBc/HBeAg-specific T-cell tolerance may have significant implications for natural HBV infection and especially for precore-negative chronic hepatitis.
authors.affiliation: Vaccine Research Institute of San Diego, 3030 Bunker Hill St., Suite 300, San Diego, CA 92109, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Chen
authors.forename: Matti
authors.initials: M
authors.lastname: Sällberg
authors.forename: Janice
authors.initials: J
authors.lastname: Hughes
authors.forename: Joyce
authors.initials: J
authors.lastname: Jones
authors.forename: Luca G
authors.initials: LG
authors.lastname: Guidotti
authors.forename: Francis V
authors.initials: FV
authors.lastname: Chisari
authors.forename: Jean-Noel
authors.initials: JN
authors.lastname: Billaud
authors.forename: David R
authors.initials: DR
authors.lastname: Milich
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D005260:Female; D006510:Hepatitis B Antibodies / Q000096:biosynthesis; D006512:Hepatitis B Core Antigens / Q000235:genetics / Q000276:immunology*; D006513:Hepatitis B e Antigens / Q000235:genetics / Q000276:immunology*; D006515:Hepatitis B virus / Q000276:immunology*; D007108:Immune Tolerance; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D011247:Pregnancy; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D006510:Hepatitis B Antibodies; D006512:Hepatitis B Core Antigens; D006513:Hepatitis B e Antigens; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins