Phylogenetic analysis of hepatitis A virus in sera from patients with hepatitis A of various severities.

Background: We analysed the association of the 5′ nontranslated region (5′NTR), nonstructural proteins 2B and 2C of the hepatitis A virus (HAV) genome, whose mutations have previously been shown to be important for enhanced replication in cell culture systems, in order to align all our data and examine whether genomic differences in HAV are responsible for the range of clinical severities. Methods: Our accumulated HAV strains of 5′NTR [nucleotide(nt) 200 and 500], entire 2B and 2C from 25 Japanese patients with sporadic hepatitis A, consisting of seven patients with fulminant hepatitis (FH), five with severe acute hepatitis (AHs) and 13 with self-limited acute hepatitis (AH), in whom the sequences of all three regions were available, were subjected to phylogenetic analysis. Results: Fulminant hepatitis patients had fewer nucleotide substitutions in 5′NTR, had a tendency to have more amino acid (aa) substitutions in 2B and had fewer aa substitutions in 2C than AH patients. Four FH and two AHs with a higher viral replication were located in the near parts of the phylogenetic trees, indicating the association between the severity of hepatitis A and genomic variations in 5′NTR, 2B and 2C of HAV. Conclusions: Our study suggests that genetic variations in HAV not in one specific region but in 5′NTR, 2B and 2C might cooperatively influence replication of the virus, and thereby affect virulence. Viral factors should be considered and examined when discussing the mechanisms responsible for the severity of hepatitis A.