title: Reduced antigenicity of the hepatitis B virus HBsAg protein arising as a consequence of sequence changes in the overlapping polymerase gene that are selected by lamivudine therapy.
abstract: The prevalence of hepatitis B virus vaccine escape mutants has increased as a consequence of the introduction of global vaccination programs. Furthermore and as a consequence of the organization of the genome of hepatitis B virus (HBV) into overlapping reading frames, the selection of polymerase mutants during long-term lamivudine therapy can select viruses with changes in the overlapping S gene coding for the hepatitis B small antigen (HBsAg). We have investigated the role of lamivudine in selecting HBV mutants with antigenically altered HBsAg protein using pooled human vaccine sera in enzyme immunosorbent assays and radioimmunoassays. HBsAg proteins containing the vaccine escape mutations G145R and D144E/G145R demonstrated markedly reduced binding to anti-HBs antibody. HBsAg mutants including E164D, W196S, I195M, M198I, and E164D/I195M (corresponding to the polymerase protein changes of V519L, M550I, L526M/M550V V553I, and V519L/L526M/M550V) selected during lamivudine treatment also demonstrated reduced binding to anti-HBs antibody. These findings raise the possibility of lamivudine-resistant mutants arising that possess antigenically distinct HBsAg proteins.
authors.affiliation: Department of Medicine (RMH), University of Melbourne, Parkville, Victoria 3050, Australia. josepht@unimelb.edu.au
authors.forename: Joseph
authors.initials: J
authors.lastname: Torresi
authors.forename: Linda
authors.initials: L
authors.lastname: Earnest-Silveira
authors.forename: Georgia
authors.initials: G
authors.lastname: Deliyannis
authors.forename: Kristy
authors.initials: K
authors.lastname: Edgtton
authors.forename: Hui
authors.initials: H
authors.lastname: Zhuang
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Locarnini
authors.forename: Janet
authors.initials: J
authors.lastname: Fyfe
authors.forename: Tina
authors.initials: T
authors.lastname: Sozzi
authors.forename: David C
authors.initials: DC
authors.lastname: Jackson
mesh_terms: D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D024882:Drug Resistance, Viral / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D006510:Hepatitis B Antibodies / Q000276:immunology; D006514:Hepatitis B Surface Antigens / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology; D016297:Mutagenesis, Site-Directed; D011863:Radioimmunoassay; D011994:Recombinant Proteins / Q000276:immunology; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D014611:Vaccination
chemical_list: D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D004259:DNA-Directed DNA Polymerase