Variability and pathogenicity of Hepatitis E virus genotype 3 variants

Infection with hepatitis E virus can be clinically inapparent or produce symptoms and signs of hepatitis of varying severity and occasional fatality. This variability in clinical outcomes may reflect differences in host susceptibility or the presence of virally-encoded determinants of pathogenicity. Analysis of complete genome sequences supports the division of HEV-3 variants into three major clades; 3-ra comprising HEV isolates from rabbits, and 3-efg and 3-abchij comprising the corresponding named subtypes derived from humans and pigs. Using this framework we investigated associations between viral genetic variability of HEV genotype 3 (HEV-3) in symptomatic and asymptomatic infections by comparing HEV-3 subgenomic sequences previously obtained from blood donors (BD) with those from patients presenting with hepatitis (H) in the United Kingdom (54 BD, 148 H), the Netherlands (38 BD, 119 H), France (24 BD, 55 H) and Germany (14 BD, 36 H). In none of these countries was evidence found for a significant association between virus variants and patient group (P>0.05 Fishers' exact test). Furthermore, within a group of 123 Scottish patients with clinically apparent HEV infections, we found no evidence for an association between variants of HEV-3 and disease severity or ALT level. The lack of detectable virally-encoded determinants of disease outcomes in HEV-3 infection implies a more important role for host factors in its clinical phenotype.