Insights From Deep Sequencing of the HBV Genome—Unique, Tiny, and Misunderstood

Abstract

Hepatitis B virus (HBV) is a unique, tiny, partially double-stranded, reverse-transcribing DNA virus with proteins encoded by multiple overlapping reading frames. The substitution rate is surprisingly high for a DNA virus, but lower than that of other reverse transcribing organisms. More than 260 million people worldwide have chronic HBV infection, which causes 0.8 million deaths a year. Because of the high burden of disease, international health agencies have set the goal of eliminating HBV infection by 2030. Nonetheless, the intriguing HBV genome has not been well characterized. We summarize data on the HBV genome structure and replication cycle, explain and quantify diversity within and among infected individuals, and discuss advances that can be offered by application of next-generation sequencing technology. In-depth HBV genome analyses could increase our understanding of disease pathogenesis and allow us to better predict patient outcomes, optimize treatment, and develop new therapeutics.

Molecular epidemiology of hepatitis B virus mutants associated with vaccine escape, drug resistance and diagnosis failure

“…Based on genetic divergence, HBV has been classified into 9 genotypes designated A‐I defined by >8% divergence at the nucleotide level and several subgenotypes, while another putative genotype, “J,” has been proposed after isolation from one individual . Genotypes and subgenotypes have a restricted ethnic‐geographical distribution …”

Analysis of genomic-length HBV sequences to determine genotype and subgenotype reference sequences

“…The scale bar indicates the estimated nucleotide substitutions per site. We were unable to verify the subgenotype of two genotype C clades, and these have been designated unassigned clade 1 and 2 (unassigned_C (1) and unassigned_C (2), respectively).…”

“…In this study, we used strong bootstrap support (≥70) and monophyletic clustering to identify distinct clades and examined the pre-existing literature for the likely subgenotype designation. In instances when subgenotypes can be seen to split into distinct clades but genetic distance and poor bootstrap support do not suggest a unique subgenotype, such as in the case of subgenotypes A1 (Fig 2) and C2 (Fig 4), we have referred to these as ‘A1 (1)’ and ‘A1 (2)’.…”

“…Hepatitis B virus (HBV) is the prototype virus of the hepadnaviridae family, an unusual family of partially double-stranded (ds)DNA viruses approximately 3.2kb in length encoding four genes, including a reverse transcriptase, encoded in overlapping reading frames on a circular genome (1,2). To date, 9 genotypes of HBV have been characterised (A-I), along with a putative 10 th genotype (J) (3).…”

“…To date, 9 genotypes of HBV have been characterised (A-I), along with a putative 10 th genotype (J) (3). The viruses display a relatively high amount of variation for a dsDNA virus (4), with the viral genotypes being further subdivided into upwards of 30 subgenotypes, many of which have distinct geographic and clinical associations (2).…”