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Abstract
Hepatitis A virus (HAV) is the most common cause of infectious hepatitis throughout the world, spread largely by the fecal-oral route. To characterize the genetic diversity of the virus circulating in China where HAV in endemic, we selected the outbreak cases with identical sequences in VP1-2A junction region and compiled a panel of 42 isolates. The VP3-VP1-2A regions of the HAV capsid-coding genes were further sequenced and analyzed. The quasispecies distribution was evaluated by cloning the VP3 and VP1-2A genes in three clinical samples. Phylogenetic analysis demonstrated that the same genotyping results could be obtained whether using the complete VP3, VP1, or partial VP1-2A genes for analysis in this study, although some differences did exist. Most isolates clustered in sub-genotype IA, and fewer in sub-genotype IB. No amino acid mutations were found at the published neutralizing epitope sites, however, several unique amino acid substitutions in the VP3 or VP1 region were identified, with two amino acid variants closely located to the immunodominant site. Quasispecies analysis showed the mutation frequencies were in the range of 7.22x10-4 -2.33x10-3 substitutions per nucleotide for VP3, VP1, or VP1-2A. When compared with the consensus sequences, mutated nucleotide sites represented the minority of all the analyzed sequences sites. HAV replicated as a complex distribution of closely genetically related variants referred to as quasispecies, and were under negative selection. The results indicate that diverse HAV strains and quasispecies inside the viral populations are presented in China, with unique amino acid substitutions detected close to the immunodominant site, and that the possibility of antigenic escaping mutants cannot be ruled out and needs to be further analyzed.
Highlights
Hepatitis A virus (HAV) infection is the most common cause of acute viral hepatitis throughout the world, and remains a significant health problem worldwide
A, with of 40 isolates grouped into sub-genotype IA diverging by roughly 0-6.0% when compared pairwise with the IA Chinese HAV isolates and with the reference IA strains from Genbank, 2 isolates grouped into sub-genotype IB diverging by roughly 0-0.4% when compared pairwise with the reference IB strains and with the IB Chinese HAV isolates
Part of the hepatitis A outbreak cases with identical sequences in the VP1-2A junction region reported from 2003 to 2010 in China were selected for further analysis in the complete VP3-VP1-2A regions
Summary
Hepatitis A virus (HAV) infection is the most common cause of acute viral hepatitis throughout the world, and remains a significant health problem worldwide. It is spread largely by the fecal-oral route, and contaminated water and food frequently cause community-wide outbreaks [1,2,3,4]. In natural infection HAV appears to elicit antibodies directed predominantly towards one conserved immunodominant neutralization region. This collection of overlapping epitopes appears to be conformation dependent and distributed over the VP1 and VP3 proteins. Studies of murine monoclonal antibody binding have identified multiple epitopes within this region, and there is evidence for a second, possibly independent site [8,9,10]
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