Five subgenotypes of hepatitis B virus genotype B with distinct geographic and virological characteristics

Several hepatitis B virus (HBV) subgenotypes, HBV/A1, A2, Bj and Ba, have been reported with respect to clinical differences among patients infected with these subgenotypes. The population genetics and phylogeography of HBV were investigated based on the complete genome sequences of 484 isolates with 108 from our chronic hepatitis B patients and the remaining from the GenBank database. Besides genotypes A–H (HBV/A–H), five subgenotypes were identified among 169 HBV/B isolates by phylogenetic analysis and nucleotide divergence. There were 27 isolates of subgenotype B1 (HBV/B1) restricted to Japan, 104 isolates of HBV/B2 with the widest distribution in most Asian countries, 4 isolates of HBV/B3 restricted to Indonesia, 32 isolates of HBV/B4 restricted to Vietnam, and 7 isolates of HBV/B5 restricted to Philippines. HBV/B2–B5 isolates carried a recombination with HBV/C over the precore and core genes. In addition to the characteristics of HBV/B1–B5 at some cis-acting elements, the precore stop-codon mutant (G1896A) was significantly different among HBV/B1, HBV/B2, and HBV/B4 (70.3%, 31.7%, 53.0%, P = 0.001), while no such mutation was found in HBV/B3 and B5. Among characteristics of the HBV/B1–B5 amino acid sequences, serotype adw (K122) was exclusive among HBV/B1, HBV/B2, and HB V/B3 isolates, while serotype ayw (R122) was among the HBV/B4 and HBV/B5 isolates. Furthermore, distinct variations of T cell and B cell recognition epitopes within surface and core proteins were also found among these subgenotypes. In conclusion, subgenotypes HBV/B1–B5 exhibited distinct geographical distributions, virologic characteristics, and probable clinical implications.