The variability of hepatitis B envelope is associated with HBs antigen persistence in either chronic or acute HBV genotype A infection

- More frequent mutations in S gene in AHBV developing chronic infection.
- More frequent mutations in MHR in non-resolvers, whatever clinical profile.
- Higher percentage of MHR haplotypes with reduced antigenicity in non-resolvers.
- Deletions and truncated proteins mainly found in non-resolver patients.
- Mean evolutionary divergence in HBsAg was lower for HBV genotype A than genotype D.

BackgroundMore than 240 million people are chronically infected by hepatitis B virus (HBV) worldwide. Envelope proteins play a crucial role in viral cellular entry and immune recognition. The loss of HBs antigen (HBsAg) correlated with a good clinical prognosis is rarely achieved with or without treatment (3-16%).ObjectivesHBV envelope variability was investigated according to HBsAg persistence.Study designThe cohort consisted of 15 HBV genotype A-infected patients divided into “resolvers”, with HBsAg clearance, and “non-resolvers”, with HBsAg persistence and in subgroups: acute (n = 5, AHBV) or chronic infection (n = 4, CHBV) and HBV/HIV coinfection (n = 6, CHBV/HIV). HBV S and preS sequences were studied by direct and ultra-deep sequencing. Amino acid sequences were analyzed with bioinformatics for predicted antigenicity.ResultsIn S gene, the complexity was lower in AHBV than in chronic-infected patients (p = 0.046). Major mutations, detected using direct sequencing, were more frequent in AHBV developing chronicity (p = 0.01) than in AHBV resolvers. In the Major Hydrophilic Region, more frequent mutations were observed in non-resolvers versus resolvers (p = 0.047) and non-resolvers tended to have more haplotypes with a reduced predicted antigenicity (p = 0.07). Most of the mutations in preS/S region were found rather in epitopic than in non-epitopic areas (p = 0.025). Interestingly, the mutation sY161F found in 3/8 non-resolvers was associated with a decrease in predicted antigenicity (28%; AnTheProt).ConclusionsHBsAg persistence was correlated with mutations and deletions in areas playing a key role in immune recognition. These data suggest that variability in HBV envelope could favor immune escape in various clinical settings of HBV genotype A-infected patients.