title: Immune and viral profile from tolerance to hepatitis B surface antigen clearance: a longitudinal study of vertically hepatitis B virus-infected children on combined therapy.
abstract: The aim of the study was to investigate longitudinally hepatitis B virus (HBV)-specific T-cell reactivity and viral behavior versus treatment response in tolerant children during combined antiviral therapy. Twenty-three children with infancy-acquired hepatitis B (HBeAg(+)) belonging to a published pilot study of 1-year treatment with lamivudine/alpha interferon (IFN-α) were investigated. Five seroconverted to anti-HBs (responders). Nine were HLA-A2(+) (4 responders and 5 nonresponders). Mutations within the HBV core gene were determined at baseline in liver and in serial serum samples by direct sequencing at baseline; during treatment week 2 (TW2), TW9, TW28, and TW52; and after follow-up week 24 (FUW24) and FUW52. HBV-specific reactivity was evaluated by T-cell proliferation with 16 HBV core 20-mer overlapping peptides and by HLA-A2-restricted core(18-27) pentamer staining and CD8(+) IFN-γ enzyme-linked immunospot (ELISPOT) assay. HBV core-specific T-cell proliferative and CD8 responses were more vigorous and broader among responders than among nonresponders at TW28 and TW52, while the number of mutations within HBV core gene immunodominant epitopes was lower at TW28 and was negatively associated with HBV-specific T-cell proliferative responses at both time points. The HBV DNA viral load was negatively associated with HBV-specific T-cell proliferative and CD8 responses during treatment, especially at TW28. Treatment-induced transition from immunotolerance to HBV immune control is characterized by the emergence of efficient virus-specific immune responses capable of restraining mutations and preventing viral evasion.
authors.affiliation: Institute of Liver Studies, King's College Hospital, London SE5 9RS, UK.
authors.forename: Ivana
authors.initials: I
authors.lastname: Carey
authors.forename: Lorenzo
authors.initials: L
authors.lastname: D'Antiga
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bansal
authors.forename: Maria Serena
authors.initials: MS
authors.lastname: Longhi
authors.forename: Yun
authors.initials: Y
authors.lastname: Ma
authors.forename: Irene Rebollo
authors.initials: IR
authors.lastname: Mesa
authors.forename: Giorgina
authors.initials: G
authors.lastname: Mieli-Vergani
authors.forename: Diego
authors.initials: D
authors.lastname: Vergani
mesh_terms: D000293:Adolescent; D000998:Antiviral Agents / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D005260:Female; D006509:Hepatitis B / Q000188:drug therapy* / Q000276:immunology* / Q000635:transmission / Q000821:virology; D006510:Hepatitis B Antibodies / Q000276:immunology; D006512:Hepatitis B Core Antigens / Q000235:genetics / Q000276:immunology; D006514:Hepatitis B Surface Antigens / Q000235:genetics / Q000276:immunology*; D006515:Hepatitis B virus / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D018445:Infectious Disease Transmission, Vertical; D016898:Interferon-alpha / Q000627:therapeutic use; D019259:Lamivudine / Q000627:therapeutic use; D008137:Longitudinal Studies; D008297:Male; D009154:Mutation; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology
chemical_list: D000998:Antiviral Agents; D006510:Hepatitis B Antibodies; D006512:Hepatitis B Core Antigens; D006514:Hepatitis B Surface Antigens; D016898:Interferon-alpha; D019259:Lamivudine