Genomic Analysis of Hepatitis B Virus Reveals Antigen State and Genotype as Sources of Evolutionary Rate Variation

Abstract

Hepatitis B virus (HBV) genomes are small, semi-double-stranded DNA circular genomes that contain alternating overlapping reading frames and replicate through an RNA intermediary phase. This complex biology has presented a challenge to estimating an evolutionary rate for HBV, leading to difficulties resolving the evolutionary and epidemiological history of the virus. Here, we re-examine rates of HBV evolution using a novel data set of 112 within-host, transmission history (pedigree) and among-host genomes isolated over 20 years from the indigenous peoples of the South Pacific, combined with 313 previously published HBV genomes. We employ Bayesian phylogenetic approaches to examine several potential causes and consequences of evolutionary rate variation in HBV. Our results reveal rate variation both between genotypes and across the genome, as well as strikingly slower rates when genomes are sampled in the Hepatitis B e antigen positive state, compared to the e antigen negative state. This Hepatitis B e antigen rate variation was found to be largely attributable to changes during the course of infection in the preCore and Core genes and their regulatory elements.

The genome of a Mesozoic paleovirus reveals the evolution of hepatitis B viruses

“…By combining pairwise HAS divergences (Supplementary Table S3) with the dating of the upper and lower boundaries of each HBV endogenization event, we calculated long-term nucleotide substitution rates (Supplementary Table S3) during the different prehistoric chapters of HBV evolution (Fig. 1) 7 (based on pairwise comparisons of eZHBVs versus extant avian HBVs) and suggest that the Mesozoic and Cenozoic longterm substitution rates of Hepadnaviridae are more than 1,000-fold slower 7 than the extant short-term substitution rates of human HBVs 16 , even during their e-antigen positive phase 17 .…”

Origins and Evolution of Hepatitis B Virus and Hepatitis D Virus

“…There are two important observations to support this claim. First, mutation rates can vary by at least one order of magnitude if the HBV genome sequences used for inferencing were from individuals in the HBeAg-negative phase (anti-HBe-positive) of disease instead of being in the asymptomatic HBeAg-positive phase (10 24 vs. 10 25 substitutions per site per year [s/s/y], respectively) (Harrison et al 2011). …”

Investigation of a Novel Hepatitis B Virus Surface Antigen (HBsAg) Escape Mutant Affecting Immunogenicity

“…It is around 42 nm in diameter with an icosahedral nucleocapsid. The HBV genome contains only 3.2 kb of partially double-stranded circular DNA, which includes four alternative overlapping open reading frames (ORFs) and replicates through an RNA intermediate [3, 4]. The viral genome is then transported into the host cell nucleus to form a complete and covalently closed circular DNA (cccDNA).…”

“…The MHR of HBsAg contains a highly conformational B-cells epitope cluster that is the main target of neutralizing antibodies to HBsAg [16, 17]. The high mutation rate due to lack of proofreading activity of HBV polymerase causes frequent mutations in the S domain of HBsAg, as it is overlapped completely by the polymerase gene [3, 18]. Mutation in the MHR alters the antigenicity and the antibody-binding specificity and leads to a failure of HBV detection (diagnostic escape) by conventional routine diagnostic HBsAg assays [17, 19–21].…”