Evolution of hepatitis B virus during primary infection in humans: Transient generation of cytotoxic T-cell mutants

Background & Aims: Acute hepatitis B is a highly dynamic human viral infection during which the hepatitis B virus can generate many genetic variants. Methods: We analyzed the evolution of the hepatitis B virus genome in sequential serum samples from a unique cohort of patients with acute infection acquired from a single source. Results: We showed that most mutations were nonsynonymous, that genetic diversity was greatest at the peak of viremia, and that patients who resolved their infection (''resolvers'') showed a significantly higher level of diversity in the core, surface, and polymerase genes compared with those who progressed to chronic infection. Overall, the core gene showed the greatest genetic diversity. In resolvers who possessed an HLA-A*0201 haplotype, the emergence of mutants in the immunodominant HLA-A*0201-restricted core 18-27 epitope was observed. Functional studies showed that these mutants were less able to stimulate interferon-@c release from core 18-27 specific CD8^+ T-cell lines. However, they appeared only as a transient low-abundance species and were rapidly displaced by wild-type sequences before resolution of infection, and their overall significance is uncertain. Conclusions: Overall, genetic evolution of the hepatitis B virus differs at early time points between patients who experience acute resolving hepatitis B and those who progress to chronicity. These observations suggest that the rapid development of broadly reactive host immune responses leads to clearance of hepatitis B virus, even in the presence of possible CD8^+ T-cell immune escape variants.