ANALYSIS OF HEPATITIS-B VIRUS POPULATIONS IN AN INTERFERON-ALPHA-TREATED PATIENT REVEALS PREDOMINANT MUTATIONS IN THE C-GENE AND CHANGING E-ANTIGENICITY

It is largely unknown whether hepatitis B virus (HBV) sequence variati on during chronic infection hampers HBV immune recognition or the anti viral effect of cytokines on HBV production. Here we have analyzed whi ch region of the HBV genome changes most drastically during an interfe ron-alpha (IFN alpha)-stimulated immune response. In addition, we have investigated whether the mutations affect viral replication, gene exp ression, and immune recognition of the mutant viral proteins. The stud y was performed with full-length HBV genomes taken longitudinally from a patient who transiently cleared HBV and seroconverted to anti-HBe d uring a long-term IFN alpha treatment. We found a replacement of the p redominant virus population during IFN alpha therapy. The virus popula tions differed mainly by a cluster of nucleotide changes in the C-gene and a pre-S2 deletion. Most of the newly emerging mutations localized within core/HBe B-cell epitopes, changed HBe antigenicity toward mono -and polyclonal antibodies, and also influenced the reactivity of the anti-HBc/e antibodies of the patient. All genomes tested expressed les s HBeAg than wild-type HBV, while replication and IFN alpha susceptibi lity were similar. These data indicate that IFN alpha therapy can lead to the emergence of HBV variants with mutations mainly affecting reco gnition of the core/HBe proteins by antibodies. Taken together, the ty pe of core/HBe-specific B-cell immune response, the sequence of the co rresponding epitopes, and the HBe expression level appear to contribut e to the decision on viral clearance or persistence. (C) 1998 Academic Press.