Hepatitis B virus genotype A rarely circulates as an HBe-minus mutant: possible contribution of a single nucleotide in the precore region.
The emergence of HBe-minus hepatitis B virus (HBV) mutants, usually through a UAG nonsense mutation at codon 28 of the precore region, helps the virus to survive the anti-HBe immune response of the host. Host and viral factors that predispose to the emergence of such mutants are not well characterized. The fact that the precore region forms a hairpin structure essential for the packaging of viral pregenomic RNA may explain the extremely high prevalence of the UAG mutation at codon 28. It converts a wobble U-G pair in the packaging signal between nucleotide 3 of codon 15 (CCU) and nucleotide 2 of codon 28 (UGG) into a U-A pair. Since genotype A of HBV has a CCC sequence at codon 15, the UAG mutation would, instead, disrupt a C-G pair present in the wild-type virus. This alteration was shown by transfection experiments to greatly compromise the packaging of pregenomic RNA. The implication of this finding was elucidated by molecular epidemiological studies. Genotype A was found to be the most prevalent genotype in the wild-type virus populations in France but was found in only 1 of the 46 isolates of HBe-minus mutants found there. These mutants were contributed chiefly by genotype D, the second most prevalent genotype in France, which is characterized by a CCU sequence at codon 15. The role of the single nucleotide at codon 15 was confirmed by the finding of the single genotype A isolate in which both wild-type and mutant viruses were present. Interestingly, nearly all of the mutants had a codon 15 sequence of CCU instead of the CCC present in the wild-type viruses. Our results suggest that genotype A of HBV rarely circulates as HBe-minus mutants, probably because of a requirement for a simultaneous sequence change at codon 15. These data, together with the virtual absence of genotype A in the Chinese samples examined, may provide some insights into the uneven prevalence of HBe-minus mutants in the world.
Li
J S
JS
Unité de Recherche sur les Hepatites, le SIDA et les Retrovirus Humains, Institut National de la Santé et de la Recherche Médicale 271, Lyon, France.
Tong
S P
SP
Wen
Y M
YM
Vitvitski
L
L
Zhang
Q
Q
Trépo
C
C
D001482:Base Composition; D001483:Base Sequence; D002681:China; D003062:Codon / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D005602:France; D005814:Genes, Viral; D014644:Genetic Variation; D006509:Hepatitis B / Q000097:blood / Q000382:microbiology; D006513:Hepatitis B e Antigens / Q000097:blood / Q000235:genetics*; D006515:Hepatitis B virus / Q000235:genetics* / Q000302:isolation & purification* / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides; D016133:Polymerase Chain Reaction / Q000379:methods; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics; D012689:Sequence Homology, Nucleic Acid; D014162:Transfection; D015678:Viral Structural Proteins / Q000235:genetics; D014779:Virus Replication
D003062:Codon; D004279:DNA, Viral; D006513:Hepatitis B e Antigens; D009838:Oligodeoxyribonucleotides; D012367:RNA, Viral; D015678:Viral Structural Proteins