Mutational Analysis of Hepatitis B Virus Enhancer 2

Chen, Shin-Tai; Porte, Patricia La; Yee, Jiing‐Kuan

doi:10.1006/viro.1993.1521

Cited by 12 publications

(4 citation statements)

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“…Li et al [26] reported that mutations of individual nucleotides within TGTTTGTTT (nt1719-nt1727, modified by the author of this article as nt1716-nt1724) significantly aborted the activity of ENII. However, Chen et al reported that mutations within nt1720-nt1727 resulted in no significant loss of function of ENII in their study [27]. In the present study, the nt1724 mutation was very prevalent in the HCC group.…”

Section: Discussionmentioning

confidence: 73%

Comparison of hepatitis B X gene mutation between patients with hepatocellular carcinoma and patients with chronic hepatitis B

et al. 2010

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Hepatitis B virus (HBV), a major causative agent of hepatocellular carcinoma (HCC), encodes an oncogenic X protein (HBx) that transcriptionally activates multiple viral and cellular promoters. The present study aimed to identify the specific gene mutation related to the clinical outcome of HCC. Seventy-two HBV-infected patients (38 with chronic HBV infection and 34 with HCC) with well-characterized clinical profiles were enrolled. The HBx region was amplified from patient serum samples and analyzed by sequencing. Genotypes were determined using the National Center for Biotechnology Information genotype tool. All isolates were genotype B or C. Enhancer II nucleotide substitutions in the HCC group were significantly different from those in the chronic hepatitis B (CHB) group (Ρ < 0.05). HCC patients with genotype C had a higher risk of harboring the 1762/1764 double mutation than those with genotype B. The incidence of the 1762/1764 double mutation was higher in the high viral load group (>10(6) copies/ml) than in the low viral load group (≤10(6) copies/ml) (P = 0.03). The 1762/1764 double mutations may be related to the genotype and viral load. We found significantly more direct repeat sequence 1 (DR1) nucleotide substitutions in the HCC group (32.4%, 11/34) than in the CHB group (10.5%, 4/38) (Ρ < 0.05). Patients with higher viral load and genotype C had a higher incidence of 1762/1764 double mutations, which may not be related with development of HCC. Enhancer II and DR1 may play an important role in HCC development via nucleotide substitution.

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Section: Discussionmentioning

confidence: 73%

Comparison of hepatitis B X gene mutation between patients with hepatocellular carcinoma and patients with chronic hepatitis B

et al. 2010

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“…However, this hypothesis seems unlikely, because, at least in the viral DNA isolated from PBMC, no mutations have been found in the core promoter, which directs the synthesis of the pregenomic RNA, in the liver-specific enhancer II, or in the DRs I and II, which are essential for the viral replication. [31][32][33][34][35] Nevertheless, it would have been necessary to have performed an analysis of viral DNA sequences directly isolated from liver to completely rule out this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Molecular analysis of hepatitis B virus DNA in serum and peripheral blood mononuclear cells from hepatitis B surface antigen–negative cases

et al. 2000

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We have analyzed the molecular bases of the persistence of hepatitis B virus (HBV) DNA in serum and peripheral blood mononuclear cells (PBMC) in the absence of detectable hepatitis B surface antigen (HBsAg) in hemodialysis patients and dialysis-unit staff members who had suffered acute hepatitis B that resolved previously. HBV DNA was found in both compartments by polymerase chain reaction (PCR) using primers of the pre-S/S region. Viral DNA was transcriptionally active in PBMC, because the covalently closed circular (ccc) HBV DNA, the template for the viral RNA transcription, was detected in 47% of the samples. Furthermore, all PBMC had HBV RNA. HBsAg-negative cases had statistically lower levels of HBV DNA in serum and PBMC than a control group of chronic HBsAg carriers. We have also studied the presence of immune complexes and the existence of mutations in the pre-S/S gene to explain the lack of detection of HBsAg in these cases. No serum HBsAg/hepatitis B surface antigen antibody (anti-HBs) immune complexes or mutations in the ''a'' determinant of the S gene were found. However, we have observed that all HBsAg-negative cases were infected by a mixture of the wild-type virus and a deletion mutant in the pre-S1 region. This deletion (amino acids 58-118) affects the S gene promoter, and previous in vitro studies have shown that it produces a reduction of the HBsAg synthesis. In conclusion, this work shows that the lack of detection of HBsAg in the presence of low viral levels of replication may be caused by the existence of viral genomes harboring deletions in the pre-S1 region that affect the S promoter. (HEPATOLOGY 2000;32:116-123.)Hepatitis B virus (HBV) is the prototype member of the Hepadnaviridae family of animal viruses. 1 HBV causes acute and chronic liver inflammation, and its persistence is associated with the development of hepatocellular carcinoma. 2,3 Viral genome consists in a 3.2-kb-long partially doublestranded circular DNA molecule that contains 4 overlapping open reading frames (ORF) 4,5 that codify for all viral proteins. The ORF S has 3 in-frame AUG codons that divide this ORF into 3 regions, termed pre-S1, pre-S2, and S, that encode for the viral envelope protein (hepatitis B surface antigen [HBsAg]); the ORF C has 2 initiation codons that encode the nucleocapsid protein (hepatitis B core antigen) and a soluble antigen (hepatitis B e antigen [HBeAg]); the ORF P encodes the viral polymerase; and the ORF X encodes a transcriptional transactivator (pX). HBV replicates by reverse transcription of a pregenomic RNA of 3.6 kb in length whose synthesis is directed by the core promoter. 6 Both the clearance of HBsAg from serum and the appearance of antibodies to HBsAg (anti-HBs) have been associated with a resolution of hepatitis in acute or chronic hepatitis B infection. 7,8 However, HBV DNA may persist in serum, liver, and peripheral blood mononuclear cells (PBMC) long after HBsAg has disappeared in both self-limited acute hepatitis 9-13 and after a successful antiviral treatment of chronic HBV in...

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“…Major roles for cellular transcription factors RF-X, NF1, HNF3, HNF4, and C/EBP at En I have been defined both genetically and biochemically (15, 35-37, 48, 58). More recently (5,67,68,(70)(71)(72), a second enhancer (En II) has been identified in HBV, located 5Ј to the genomic RNA start sites and at least partially coextensive with upstream activating elements of the core promoter (69). This enhancer is strongly liver specific (72) and is known to influence genomic RNA transcription; whether it plays a wider role in regulation of other viral promoters in vivo is unknown.…”

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confidence: 99%

Cellular factors controlling the activity of woodchuck hepatitis virus enhancer II

Ueda

Ganem

1996

J Virol

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Woodchuck hepatitis virus (WHV) efficiently induces hepatocellular carcinoma in chronically infected hosts. A key step in hepatocarcinogenesis by WHV is insertional activation of the cellular N-myc gene by integrated viral DNA. WHV enhancer II (En II) is the major cis-acting element involved in this activation. Here we characterize this viral enhancer element and define the cellular factors involved in its activity. WHV En II activity is strongly liver specific and maps to an 88-nucleotide DNA segment (nucleotides 1772 to 1859) located 5 to the pregenomic RNA start site. Genetic analyses and electrophoretic mobility shift assays indicate that the enhancer contains three subregions important to its activity. The core elements of the enhancer are recognition sites for the liver-enriched factors HNF1 and HNF4; together, these signals account for the bulk of En II activity as well as its strong liver specificity. Multimerization of either recognition site produced strong activity even in the absence of other En II sequences. 5 to these elements is a binding site for the ubiquitous Oct-1 transcription factor, which further augments enhancer activity ca. twofold.

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Mutational Analysis of Hepatitis B Virus Enhancer 2

Cited by 12 publications

References 0 publications

Comparison of hepatitis B X gene mutation between patients with hepatocellular carcinoma and patients with chronic hepatitis B

Comparison of hepatitis B X gene mutation between patients with hepatocellular carcinoma and patients with chronic hepatitis B

Molecular analysis of hepatitis B virus DNA in serum and peripheral blood mononuclear cells from hepatitis B surface antigen–negative cases

Cellular factors controlling the activity of woodchuck hepatitis virus enhancer II

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