Analysis of the full-length genome of genotype 4 hepatitis E virus isolates from patients with fulminant or acute self-limited hepatitis E.
It was suggested that hepatitis E virus (HEV) genotype 4 is associated more closely with the severity of hepatitis E than genotype 3, although the virological basis remains unknown. The aim of this study was to examine whether genomic differences among genotype 4 HEVs are responsible for the development of fulminant hepatitis. Full-length sequences of genotype 4 HEVs from three patients with fulminant hepatitis and six patients with acute self-limited hepatitis were determined. The sequences were analyzed with those of 13 genotype 4 HEV isolates whose entire nucleotide sequence is known. Analysis of 22 full-length sequences (fulminant hepatitis, 5; acute hepatitis, 17) revealed that C at nt 1816 and U at nt 3148 (U3148), both of which do not change the amino acid sequences, were significantly associated with fulminant hepatitis (P = 0.0489, respectively). When partial nucleotide sequences containing nt 1816 or nt 3148 were determined in 16 additional HEV isolates of genotype 4, a closer association between U3148 and fulminant hepatitis (P = 0.0018) was observed. The comparison of 86 HEV isolates of all four genotypes showed that U3148 had a stronger association with fulminant hepatitis than other nucleotides at nt 3148 (P = 0.0006). Patients infected with HEV with U3148 had a significantly lower value of the lowest prothrombin activity (P = 0.0293). Nt 3148 is located within the RNA helicase domain, and 22-nt sequence including nt 3148 was well conserved among all genotypes. A silent substitution of U3148 in HEV may be associated with the development of fulminant hepatitis. Further studies are needed to clarify the underlying mechanism.
Inoue
Jun
J
Division of Virology, Department of Infection and Immunity, Jichi Medical School, Tochigi-Ken, Japan.
Nishizawa
Tsutomu
T
Takahashi
Masaharu
M
Aikawa
Tatsuya
T
Mizuo
Hitoshi
H
Suzuki
Kazuyuki
K
Shimosegawa
Tooru
T
Okamoto
Hiroaki
H
D000208:Acute Disease; D000368:Aged; D001483:Base Sequence; D016679:Genome, Viral; D005838:Genotype; D016751:Hepatitis E / Q000503:physiopathology* / Q000821:virology; D016752:Hepatitis E virus / Q000145:classification / Q000235:genetics / Q000302:isolation & purification / Q000472:pathogenicity; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010802:Phylogeny; D017422:Sequence Analysis, DNA; D012720:Severity of Illness Index