Selection for a pre-C stop codon mutation in a hepatitis B virus variant with a pre-C initiation codon mutation during interferon treatment.
Hepatitis B virus (HBV) variants with a stop codon, a mutated translation initiation codon or other mutations in the pre-C region which prevent e-antigen expression are highly prevalent in anti-HBe chronic carriers and can be positively selected from a mixed virus infection. Our laboratories recently described pre-C variants with two pre-C mutations which prevent HBeAg expression. Here we have investigated whether there is a selective pressure for acquisition of the second pre-C mutation. By direct sequencing of amplified HBV DNA from sera of a chronic carrier taken during a 6-year follow-up, we found that genomes of a virus population virtually all had a pre-C translation initiation codon mutation and about 50% had an additional stop codon mutation. With the onset of interferon treatment, the genomes with the stop codon mutation increased to more than 95% while the frequency of the translation initiation codon mutation in all genomes remained constant. These data indicate positive selection (possibly immune-mediated and HBeAg-targeted) for a second pre-C mutation. This putative enhancement of negative translational control may be present because a pre-C translation initiation codon mutation cannot totally prevent HBeAg expression and is therefore less frequent.
Santantonio
T
T
Max-Planck-Institut für Biochemie, Martinsried/München, Federal Republic of Germany.
Jung
M C
MC
Schneider
R
R
Pastore
G
G
Pape
G R
GR
Will
H
H
D000328:Adult; D001483:Base Sequence; D002353:Carrier State; D003062:Codon / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics / Q000302:isolation & purification; D005500:Follow-Up Studies; D014644:Genetic Variation; D006509:Hepatitis B / Q000382:microbiology / Q000628:therapy*; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D007372:Interferons / Q000627:therapeutic use*; D008297:Male; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009838:Oligodeoxyribonucleotides; D016133:Polymerase Chain Reaction / Q000379:methods; D012641:Selection, Genetic
D003062:Codon; D004279:DNA, Viral; D009838:Oligodeoxyribonucleotides; D007372:Interferons