Variability in hepatitis B virus DNA: phylogenetic, epidemiological and clinical implications

Hepatitis B virus has the smallest of all known human DNA virus genomes (3.2 kb) and a unique replication strategy with an intermediate reverse transcription step. The naturally occurring genetic variability between different HBV strains provides the basis for phylogenetic analysis. Four main genotypes of HBV have been found, with the possible existence of 1 or 2 more. The different genotypes largely follow a distinctive geographical distribution. Point mutations and nucleotide deletions in the genes (pre-S and S) encoding different forms of the surface protein have been shown to arise both spontaneously and after interferon treatment or vaccination. An immune escape mechanism is believed to be the reason for these mutations. The clinical implications of variations in the HBV X gene have not been widely studied, but these variations may be of importance in the development of hepatocellular carcinoma. Seroconversion from HBeAg to anti-HBe can be correlated with specific changes in the core promoter, and/or with a translational stop in precore codon 28. In both cases the production of HBeAg protein would be shut off. Mutations in the precore region may have a larger impact at another level, by inhibiting or enhancing viral replication through changes in folding of the transcript.