Genetic characterization of hypervariable region 1 in patients chronically infected with hepatitis C virus genotype 2.

The hypervariable region 1 (HVR1) has been most reliably identified in the genome of HCV genotype 1 isolates and thought to possibly play a role in immune evasion and development of chronic infection. There are few studies, however, of other HCV genotypes to determine if they also have such a hypervariable region present, and it is unclear whether or not there is any genotype-dependent difference in the genetic characteristics of HVR1. We determined the nucleotide sequence of 5' end of E2/NS1 region of the HCV genome spanning HVR1 of multiple genotype 1 and 2 HCV isolates and carried out a detailed genetic analysis. Similarity plots identified two hypervariable regions within the genotype 2 sequences, a larger one corresponding to HVR1 as well as a smaller 27-nucleotide region of hypervariability. The synonymous substitutions per synonymous site (ds) was greater than nonsynonymous substitutions per nonsynonymous site (dn) within genotype 1 group whereas dn and ds were similar in the genotype 2 group. Analysis of amino acid sequences revealed several conserved sites across genotype 1 and 2 (amino acid numbers 2,6, 20 and 26) and overall similar hydropathic profiles were found within two genotypes. Still, despite the hypervariability, the HVR1 showed a genotype-specific phylogenetic clustering. Thus, HVR1 appears to be conserved between genotypes in keeping with it having an important survival function. Genotype 2 appears to have a greater rate of nonsynonymous substitutions within HVR1, suggesting a greater positive evolutionary pressure. Copyright 2001 Wiley-Liss, Inc.