Variability in the Precore and Core Promoter Region of the Hepatitis B Virus Genome

There is increasing evidence that hepatitis B virus (HBV) infections with different genotypes and subgenotypes differ in response to treatment and long-term prognosis. The differences emerge from variability within the genomes that leads to structural deviations at the pregenomic level and to changes at the translational level. Naturally occurring HBV strains covering the four major genotypes A-D were obtained from 393 patients and part of the genome was amplified using polymerase chain reaction (PCR), sequenced, and analyzed for mutational differences in the precore and core promoter regions. The study confirmed that core promoter and precore mutations occur at key positions (A1762T, G1764A, G1896A, and G1899A), and that the proportions of strains with seroconvertion in patients differ between the four HBV genotypes. A rare double mutation (C1857T together with G1897A) was observed, and C1856T was found together with the emerging G1898A mutation, which itself was found to be more widespread geographically than previously described. We found a novel mutation (T1850C), never before observed in human HBV strains but known from woodchuck hepatitis virus (WHV). A novel association of mutation C1773T with G1764T, C1766A, and G1757A was also found within a site already suggested to be a putative binding site for HNF-3. This novel association is proposed by us to be of importance for additional binding of HNH-2 to this site and is a better indicator of the emergence of the double mutation G1764T and C1766A than the G1757A mutation proposed previously. J. Med. Virol. 86:437-445, 2014. (c) 2013 Wiley Periodicals, Inc.