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Clinical significance and molecular characteristics of common hepatitis B virus variants

Anna SF Lok, MD
Section Editor
Rafael Esteban, MD
Deputy Editor
Jennifer Mitty, MD, MPH


Viral DNA and especially RNA genomes are inherently variable due to errors introduced during replication. These errors are in the range of 1 mutation in 1,000 to 100,000 nucleotides per replication cycle for RNA viruses, and approximately 1 mutation in 100,000,000 nucleotides per replication cycle for DNA viruses [1,2]. The higher mutation rate among RNA viruses is related to the lack of proofreading functions of RNA polymerases and reverse transcriptases. As a result, mutations in viral genomic sequences are generated naturally during viral replication and should be viewed as a normal biological event.

Hepatitis B virus (HBV), a member of the Hepadnaviridae family, replicates asymmetrically via reverse transcription of an RNA intermediate, making it prone to mutations [3]. The estimated mutation rate of the hepadnavirus genome is about 2 x 10(4) base substitutions/site/year, about 100 times higher than that of other DNA viruses but about 100 to 1,000 times lower than that of other RNA viruses [4]. Although mutations can occur randomly along the HBV genome, the overlapping open reading frames limit the number and location of viable mutations. Because chronic HBV infection frequently persists for decades, many variants may exist within the same host at any given time and each variant may have multiple base changes.

Selection by the host for the fittest variant occurs after the random mutation process. Fitness may be defined at the cellular level (viruses that replicate most efficiently in a cell type will predominate) or at the extra-cellular level (viruses that avoid immune elimination will become dominant) [5]. Thus, the accumulation of viral variants depends upon the rate at which the variants are generated and the advantage they confer to the virus.

The genetically different viral species concomitantly present in a single cell or in a single individual are termed quasi-species [1]. Interpretation of the clinical significance of HBV mutations is complicated by the lack of standardized nomenclature, differences in sensitivities of assays used in their detection, and the presence of mutations in more than one region of the HBV genome even in the same species [6,7]. Despite these difficulties, in vivo analyses of naturally occurring viral variants and in vitro mutagenesis studies have identified some mutations that have a role in viral latency, pathogenesis of liver disease, immune escape, and resistance to antiviral therapy. This topic review will summarize the clinical relevance and molecular characteristics of common HBV variants.


The precore/core region of the HBV genome encodes the nucleocapsid protein (HBcAg) and HBeAg [8,9]. The core open reading frame has two transcripts with heterogeneous 5' ends and two in-phase initiation codons. HBeAg is translated from the precore mRNA, producing a precursor polypeptide comprising the precore and the entire core region. The precore polypeptide is translocated into the endoplasmic reticulum by a signal peptide. Cleavage of the amino and carboxy termini results in a secretory protein, HBeAg. HBcAg is translated from the pregenomic RNA. Both HBcAg and HBeAg contain B- and T-cell epitopes, of which some are shared. (See "Characteristics of the hepatitis B virus and pathogenesis of infection".)


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Literature review current through: Sep 2016. | This topic last updated: Oct 12, 2016.
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