Evolution of hepatitis B virus during primary infection in humans: transient generation of cytotoxic T-cell mutants.
OBJECTIVE
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-gamma 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.
Whalley
Simon A
SA
Department of Hepatology, Royal Free and University College Medical School, London, England, United Kingdom.
Brown
David
D
Webster
George J M
GJ
Jacobs
Ruth
R
Reignat
Stephanie
S
Bertoletti
Antonio
A
Teo
Chong-Gee
CG
Emery
Vincent
V
Dusheiko
Geoffrey M
GM
D005075:Biological Evolution; D018984:Epitopes, T-Lymphocyte; D016679:Genome, Viral; D015234:HLA-A Antigens / Q000502:physiology; D006509:Hepatitis B / Q000276:immunology / Q000821:virology*; D006515:Hepatitis B virus / Q000235:genetics*; D006801:Humans; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014779:Virus Replication
D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens