Hepatitis B Virus Strains with Mutations in the Core Promoter in Patients with Fulminant Hepatitis

Sato, Shunichi; Suzuki, Kazuyuki; Akahane, Yoshihiro; Akamatsu, Koichi; Akiyama, Kenji; Yunomura, Kazuhiro; Tsuda, Fumio; Tanaka, Takeshi; Okamoto, Hiroaki; Miyakawa, Yuzo; Mayumi, Makoto

doi:10.7326/0003-4819-122-4-199502150-00001

Cited by 284 publications

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“…However, there is no strict association of these mutations with severe chronic hepatitis B as asymptomatic patients with anti-HBe in serum were also frequently found to be infected with such variants (Okamoto et al, 1994 ;Takahashi et al, 1995 ;Kurosaki et al, 1996). Furthermore, some but not all studies on acutely infected patients reported an association of the T-1762\A-1764 mutations with fulminant courses (Kaneko et al, 1995 ;Laskus et al, 1995 ;Sato et al, 1995). In these cases both mutations are frequently combined with a C to T exchange at position 1653 in the Cp\EnII (Ogata et al, 1993 ;Hasegawa et al, 1994 ;Kaneko et al, 1995).…”

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confidence: 99%

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.

Günther

Piwon

Will

1998

Journal of General Virology

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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

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confidence: 99%

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.

Günther

Piwon

Will

1998

Journal of General Virology

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“…23,24 Nevertheless, there remains lingering concerns that HBeAg seroconversion associated with the development of A1896 is less likely to result in remission of liver disease. Similarly, early studies reported that core promoter mutations were mainly found in patients with fulminant hepatitis or chronic active hepatitis, 12,13,15,25 but later studies showed that TA changes were also found in asymptomatic carriers. 12,14 Thus, it is unclear if TA changes influence the severity or course of liver disease after HBeAg seroconversion.…”

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confidence: 99%

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

1999

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Mutations in the core promoter and precore regions are frequently found in hepatitis B e antigen (HBeAg)-negative patients, but precore stop codon mutation is restricted to hepatitis B virus (HBV) genotypes that have T at nucleotide 1858. The aims of this study were to determine the role of core promoter and/or precore mutations in HBeAg seroconversion and their impact on the subsequent course of liver disease, and to determine if core promoter mutations are more frequently selected in patients with HBV genotypes that preclude the development of precore stop codon mutation. Serial sera from 45 patients with chronic HBV infection were polymerase chain reaction (PCR)-amplified, and the HBV core promoter and precore regions were sequenced. Ninety-two percent of patients had core promoter or precore mutations after HBeAg seroconversion: 42% had core promoter changes only, 38% had precore stop codon mutations only, and 12% had changes in both regions. Seventy-three percent of the patients had persistently normal aminotransferases, and only 8% had multiple flares in aminotransferases after HBeAg seroconversion. Core promoter changes were significantly more common in patients infected with HBV who have C at nucleotide 1858 (91% vs. 27%; P F .01), while precore stop codon changes were exclusively found in patients infected with HBV who have T at nucleotide 1858 (87% vs. 0; P F .01). The vast majority of our patients had core promoter and/or precore mutations after HBeAg seroconversion. Nevertheless, most patients had sustained remission of liver disease. Our data suggest that core promoter changes are preferentially selected in patients infected with HBV genotypes that preclude the development of precore stop codon mutation. (HEPATOLOGY 1999;29:976-984.)

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“…19,20,21 Various mutations in the first and second AT-rich region have been observed in asymptomatic HBV carriers or patients with acute or chronic hepatitis B. Of those, the paired mutations from A to T at nt 1762 and from G to A at nt 1764, as detected in 75 % of our HBeAg-minus patients, have been most frequently reported.…”

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confidence: 98%

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Poovorawan¹,

Theamboonlers²,

Jantaradsamee³

et al. 1999

ScienceAsia

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In Thailand, hepatitis B virus infection along with its fatal sequelae liver cirrhosis and hepatocellular carcinoma constitutes a public health burden of endemic proportions. The second phase of the infection is usually characterized by cessation of HBV DNA replication and seroconversion to anti-HBe. However, persistent viremia with active liver disease has been encountered in some anti-HBe positive patients, a discrepancy explained by mutations in the precore/core region of the viral genome. The resulting failure to synthesize HBeAg may help the virus evade immune clearance, while HBV replication and expression of HBcAg proceed unchecked. Discreet types of mutation in the precore/core region have been found at varying prevalence depending on the predominant HBV genotype in the respective geographical areas. The purpose of the present study has been to elucidate both prevalence and type along with the nucleotide positions of the mutations prevailing among Thai chronic hepatitis patients. We subjected 68 patients to serological tests for HBeAg, as well as semi-nested PCR with subsequent DNA sequencing. HBV DNA was detected in 87.5% of HBeAg positive and 40.9 % of HBeAg negative patients, respectively. Mutations in the core promoter amounted to 28.6 % in HBeAg positive and 75% in HBeAg negative patients, in the start codon of the precore gene to 37.5% and in codon 28 to 18.8% in HBeAg negative patients. Our results have shown mutations affecting the core promoter of HBeAg to be by far the most prevalent in Thai patients, followed by mutations of the start codon whereas those changing codon 28 into a stop codon are less frequently encountered than has been reported from other areas indicating a distinct HBV genotype prevailing in Thailand.

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Hepatitis B Virus Strains with Mutations in the Core Promoter in Patients with Fulminant Hepatitis

Abstract: In Japan, fulminant hepatitis B is closely associated with HBV strains that do not produce HBeAg because of mutations in the precore region, which affect translation of HBeAg, or because of mutations in the core promoter, which affect transcription of the HBeAg coding region.

Cited by 284 publications

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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.

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.

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

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