Variability in the precore and core promoter region of the hepatitis B virus genome

Abstract

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.

Evolution of full-length genomes of HBV quasispecies in sera of patients with a coexistence of HBsAg and anti-HBs antibodies

“…Mutations of the core promoter (CP) and precore are prevalent in HBV chronic infection 40 and the severity of liver disease associated with core promoter (T1753C, A1762T, G1764A, T1768A and A1846T/C) and precore (G1896A and G1899A) mutations has been widely discussed 41–44 . BCP A1762T/G1764A are dual mutations which enhance viral genome replication 41, 42 , and may partially resist neutralization of anti-HBs. In addition to the above mutations, the frequency of mutations (G1742A, A1755C, A1775G, C1773T and T1802C) in the experimental group was significantly higher than in the control group ( p  < 0.05).…”

Characterization of Full-Length Genomes of Hepatitis B Virus Quasispecies in Sera of Patients at Different Phases of Infection

“…During the natural course of HBV chronic infection, especially in the immunoactive phase, mutations in the core promoter (CP), precore, and core genes are most common (37). The association of hepatitis B virus mutations in the core promoter (T1753C, A1762T, G1764A, and A1846T/C) and precore regions (G1896A) with the severity of liver disease has been widely discussed (38)(39)(40)(41). The G1896A mutation resulting in reduced or absent HBeAg production may be one of the factors contributing to severe hepatitis, as both of the above mutations have been shown to upregulate viral DNA replication and reduce HBeAg production in vitro (42).…”

Mutations of Basal Core Promoter and Precore Regions in Hepatitis B Virus Genotypes B and C

“…A previous study reported that T1858C mutations are often found in combination with A1775G ( 21 ). In our results, we showed that 16 of 17 T1858C mutation-containing sequences were in T1858C/A1775G/G1721A triple mutations.…”