T1764G1766 core promoter double mutants are restricted to Hepatitis B virus strains with an A1757 and are common in genotype D

Abstract

To investigate the role of pre-core and basal core promoter (BCP) mutants in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (e-CHB) in Iran, Hepatitis B virus strains from 30 patients and 42 anti-HBe-positive asymptomatic carriers (ASCs) were characterized. G 1896 A pre-core stop mutants, detected in 77 % of e-CHB patients and 85 % of ASCs, showed no association with virus load or aminotransferase levels. Twenty per cent of e-CHB patients and 31 % of ASCs harboured T 1762 A 1764 mutants. When this double mutation was associated with G 1757 , it was linked to a higher virus load in patients than when it was associated with A 1757 (10 5?2±1?8 vs 10 3?2±0?8 copies ml "1 ; P=0?004). Interestingly, the most common BCP mutations were T 1764 and G 1766 , which were present in 33 % of e-CHB patients and 29 % of ASCs. These were associated with higher virus load and aminotransferase levels compared with patients lacking core promoter mutations, although this was not significant. The T 1764 G 1766 double mutation was only present in strains with A 1757 (P<0?001), which is more frequent in strains of genotype D than in those belonging to other genotypes. On the other hand, the T 1762 A 1764 double mutation was found more frequently in association with G 1757 than with A 1757. The T 1762 A 1764 double mutation forms a binding site for hepatocyte nuclear factor 1 (HNF1), which is constrained by A 1757. However, the T 1764 G 1766 double mutant may form a binding site for HNF3. Thus, position 1757 affects the emergence of promoter double mutants and would predict a relative genotypic restriction of both the T 1762 A 1764 and the T 1764 G 1766 double mutants.

CTL escape mutations of core protein are more frequent in strains of HBeAg negative patients with low levels of HBV DNA

“…All patients were enrolled in the study after giving informed consent. Clinical characteristics of patients were previously described 17, and all patients were shown to be infected with HBV genotype D 17.…”

“…In a recent study, we characterized the BCP and preC regions of HBV isolates of Iranian patients with e-CHB, and asymptomatic carriers (ASCs) 17. The present study investigates the prevalence of mutations in different HBc immune epitopes of HBV strains in the previously studied Iranian patients and its association to serum levels of HBV DNA, aminotransferase levels, and also BCP and preC mutational patterns.…”

“…The grouping of the shaded sequences corresponds to strains with different BCP mutants previously published. 17…”

Molecular epidemiological study of hepatitis B virus infection in two different ethnic populations from the Solomon Islands

“…Even in the same genotype, the significance of the clinical difference varied as a function of the subgenotype [Duong et al, 2004]. These findings indicate the clinical significance of subgenotypes and geographical variation in the prevalence of BCP and Pre-C mutations [Funk et al, 2002;Sendi et al, 2005]. HBV infection in the Solomon Islands is still highly endemic, and the genotype is ethnicity-specific.…”

“…However, it remains unclear whether these mutations in HBV/D could affect HBeAg secretion, because nt 1846 is located outside the encapsidation signal [Kramvis and Kew, 1998]. A recent study in an Iranian population [Sendi et al, 2005] mutations, were found against the strains in Iran. Moreover, no relation to the viral load was shown in these mutations.…”