Sequence heterogeneity is a feature of hepatitis B virus (HBV), the prototype member of the family Hepadnaviridae. Based on an intergroup divergence of greater than 7.5% across the complete genome, HBV has been classified phylogenetically into 9 genotypes, A-I, with a putative 10th genotype ‘J', isolated from a single individual. With between approximately 4 and 8% intergroup nucleotide divergence across the complete genome and good bootstrap support, genotypes A-D, F, H, and I are classified further into subgenotypes. There is a broad and highly statistically significant correlation between serological subtypes and genotypes, and in some cases, serological subtypes can be used to differentiate subgenotypes. The genotypes, and certain subgenotypes, have distinct geographical distributions and are important in both the clinical manifestation of infection and response to antiviral therapy. HBV genotypes/subgenotypes and genetic variability of HBV are useful in epidemiological and transmission studies, tracing human migrations, and in predicting the risk for the development of severe liver disease and response to antiviral therapy. Moreover, knowledge of the genotype/subgenotype is important in implementing preventative strategies. Thus, it is crucial that new strains are correctly assigned to their respective genotype/subgenotype and consistent, unambiguous, and generally accepted nomenclature is utilized.

Various genotypes of the hepatitis B virus (HBV) induce liver disease of distinct severity, but the underlying virological differences are not well defined. Huh7 cells were transfected with plasmids carrying 1.24-fold the HBV genome of different genotypes/subgenotypes (2 strains each for Aa/A1, Ae/A2, Ba/B2 and D; 3 each for Bj/B1 and C). HBV DNA levels in cell lysates, determined by Southern hybridization, were the highest for C followed by Bj/Ba and D/Ae (P < .01), and the lowest for Aa (P < .01), whereas in culture media, they were the highest for Bj, distantly followed by Ba/C/D and further by Ae/Aa (P < .01). The intracellular expression of core protein was more than 3-fold lower for Ae/Aa than the others. Hepatitis B e antigen (HBeAg) was excreted in a trend similar to that of HBV DNA with smaller differences. Secretion of hepatitis B surface antigen (HBsAg) was most abundant for Ae followed by Aa, Ba, Bj/C and remotely by D, which was consistent with mRNA levels. Cellular stress determined by the reporter assay for Grp78 promoter was higher for C and Ba than the other genotypes/subgenotypes (P < .01). Severe combined immunodeficiency mice transgenic for urokinase-type plasminogen activator (uPA/SCID), with the liver replaced for human hepatocytes, were inoculated with virions passed in mouse and recovered from culture supernatants. HBV DNA levels in their sera were higher for C than Ae by 2 logs during 4–7 weeks after inoculation. In conclusion, virological differences among HBV genotypes were demonstrated both in vitro and in vivo. These differences may influence HBV infections with distinct genotypes in clinical and epidemiological settings. (HEPATOLOGY 2006;44:915–924.)