Complete hepatitis B virus genome analysis in HBsAg positive mothers and their infants with fulminant hepatitis B

Abstract

Background: After perinatal transmission of hepatitis B virus, infants of anti-HBe positive HBsAg carrier mothers may develop fulminant hepatitis B. Previously it has been suggested, that fulminant hepatitis B in adults was associated with specific mutations in the HBV-genome. The aim of this study was to investigate, whether specific viral variants are associated with fulminant hepatitis B in young infants.

Methods: The complete HBV-genomes of five mothers and their infants with fulminant hepatitis were isolated from the sera, amplified and directly sequenced.

Results: Between 6 and 43 base pair exchanges between the HBV genomes of the infants and their mothers were identified. The mutations spread over the entire virus genome. Nucleotide exchanges in the basic core promotor and precore region were identified in all cases. A heterogeneous virus population was detected in four mothers.

Conclusions: Many new mutations were proved to emerge during fulminant hepatitis B in infants, who had been perinatally infected. HBeAg negative variants were the predominant population in all children, whereas these mutants could only be detected as subpopulations in four mothers. The data suggest that the selection of a specific HBeAg negative viral strain may be associated with the development of fulminant hepatitis B in children.

Figure 1

Nucleotide Exchanges between mothers (M1–M5) and their infants (1–5) in comparison with the Reference Sequence. Nucleotide positions are according to the nomenclature of Galibert et al. 1979. Mutations occurring in the HBV genomes of both, mother and child-compared to the reference sequence, are not listed. Nucleotide positions with a heterogeneous HBV population are shown in italics.

Figure 2

Mutations identified in the HBV genomes from mothers and infants are illustrated. (C)The horizontal line represents the HBV nucleotide sequence of the reference genome (11). (A) The four open reading frames (ORF) are depicted in open bars. Lines within these bars represent mutations resulting in amino acid changes in the infant with fulminant disease. (B) Black bars in the middle indicate enhancer and promotor regions (GRE: Glucocorticoid response element, ENH I-XP: enhancer I and X promotor, ENH II-CP: enhancer II and core promotor, ε: pregenome RNA encapsidation signal epsilon, SP I: surface promotor I, SP II: surface promotor II).

Figure 3

Amino acid exchanges between mothers and their infants in comparison to the Reference Sequence. Amino acid positions are numbered from the start codon of each protein. Only amino acid exchanges from mothers (M1–M5) to their infants (1–5) are depicted, the reference sequence according to Galibert et al.(1979) is listed for comparison; a heterogeneous population according to the nucleotide sequence is shown in italics.* = stop ; met = start codon, **aa exchange prevents preS2 production.