Wild-type levels of pregenomic RNA and replication but reduced pre-C RNA and e-antigen synthesis of hepatitis B virus with C(1653) --> T, A(1762) --> T and G(1764) --> A mutations in the core promoter.

Abstract

Hepatitis B virus (HBV) isolates with A-1762 to T and G-1764 to A mutations in the core promoter have been associated with active hepatitis, severe liver disease following liver transplantation, hepatocellular carcinoma and acute fulminant courses -in the latter case combined with a C-1653 to T mutation. In this study, a mutant core promoter region containing the T-1653, T-1762 and A-1764 mutations was placed into the context of a wild-type HBV genome and analysed by transfection. The mutations reduced the level of pre-C mRNA (by 55 %) and e-antigen secretion. In contrast, no significant effects on the levels of pregenome/C and pre-S/S mRNAs, intracellular core, polymerase, and pre-S1/S2 proteins and secreted S-antigen were observed. The amount of progeny virus DNA in the cells and in the culture medium was increased marginally, if at all.Mutations in the core promoter\enhancer II (Cp\EnII) of hepatitis B virus (HBV), namely an A to T change at position 1762 combined with a G to A change at position 1764, were assumed to play a role in HBV pathogenesis. They were frequently observed in chronically infected patients with active liver disease, severe recurrent liver disease following liver transplantation or hepatocellular carcinoma, but not or rarely in asymptomatic hepatitis B e-antigen (HBeAg)-positive patients (Horikita et al

Mutations of the core promoter and response to interferon treatment in chronic replicative hepatitis B

“…It has been shown in vivo and in vitro that the 1762 and 1764 mutations cause a reduction of circulating HBeAg by suppressing precore RNA transcription. 27,[35][36][37][38][39] A marked reduction of HBeAg was seen in our HBeAg-positive patients carrying mutations at nt 1762 and 1764 (Table 4). On the other hand the 1762 and 1764 mutations have been shown in transfection studies to increase viral replication by enhancing pregenome transcription 39,40 or virus encapsidation.…”

Different hepatitis b virus genotypes are associated with different mutations in the core promoter and precore regions during hepatitis B e antigen seroconversion

“…The TA changes decrease, but do not completely abolish, HBeAg secretion. [16][17][18][19][20] Thus, additional steps such as immune clearance or development of other mutations such as A1896 may be needed for HBeAg clearance. An isolated A1764 change has also been reported in a small percentage of patients by other investigators.…”

“…TA changes in the core promoter region have been reported to be associated with enhanced replication in in vitro studies, 16,17,19 but these findings have been refuted by other investigators. 18 TA changes have also been postulated to alter the secondary structure of the 3Ј-end of the pregenomic RNA, thus facilitating DNA minus-strand translocation to DR1, 30 but these effects have not been proven.…”

“…This hypothesis is supported by in vitro observations that the TA changes decrease transcription of precore mRNA and secretion of HBeAg. [16][17][18][19][20] However, TA changes have also been found in some HBeAg-positive patients, especially those with chronic hepatitis. 12,13 Thus, the role of core promoter mutations in HBeAg clearance is unclear.…”

A mathematical model of the intracellular replication and within host evolution of hepatitis type B virus: Understanding the long time course of chronic hepatitis

“…The intracellular dynamics of HBV replication may be changed when the mutation in the promoter region affecting on the promoter activity is accumulated. The phenotype of HBV such as viral gene expression pattern is changed by the mutation (Buckwold et al, 1996;Hasegawa et al, 1994;Moriyama et al, 1996;Günther et al, 1998;Jammeh et al, 2008). Therefore we next consider the effect of evolutionary change of HBV within host for clinical course of hepatitis.…”