A case-control study for differences among hepatitis B virus infections of genotypes A (subtypes Aa and Ae) and D †

Tanaka, Yasuhito; Hasegawa, Izumi; Kato, Takanobu; Orito, Etsuro; Hirashima, Noboru; Acharya, Subrat Kumar; Gish, Robert G.; Kramvis, Anna; Kew, Michael C.; Yoshihara, Namiko; Shrestha, Santosh Man; Khan, Mobin; Miyakawa, Yuzo; Mizokami, Masashi

doi:10.1002/hep.20365

Cited by 140 publications

(169 citation statements)

References 49 publications

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“…These findings are consistent with the fact that genotype Aa, which often has T1862 as its wild-type sequence, continues to express HBeAg (25,27). Do mutations at nucleotides 1862, 1863, and 1869 just down regulate core protein expression?…”

Section: Discussionsupporting

confidence: 78%

“…Introduction of the G1899A mutation overcomes the replication defect of these mutants. The G1862T mutation is frequently associated with a G1888A or G1899A covariation (8,14,25,27,33). While the G1888A mutation is silent at the amino acid level, the G1899A mutation induces a pcG29D substitution in the terminal residue of the precore peptide (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…Aromatic and charged residues introduced into these positions often abolish cleavage or alter the cleavage site (6). Molecular epidemiological studies have revealed, with the exception of the African/Asian subgroup of genotype A (genotype Aa), the rise of the G1862T mutation only at the anti-HBe stage of infection (14,25,27,33). The corresponding V17F substitution in the precore peptide generates a "forbidden" residue at the Ϫ3 position.…”

Section: Resultsmentioning

confidence: 99%

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Point Mutations Upstream of Hepatitis B Virus Core Gene Affect DNA Replication at the Step of Core Protein Expression

Guarnieri

Kim

Bang

et al. 2006

J Virol

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The pregenomic RNA directs replication of the hepatitis B virus (HBV) genome by serving both as the messenger for core protein and polymerase and as the genome precursor following its packaging into the core particle. RNA packaging is mediated by a stem-loop structure present at its 5 end designated the signal, which includes the core gene initiator AUG. The precore RNA has a slightly extended 5 end to cover the entire precore region and, consequently, directs the translation of a precore/core protein, which is secreted as e antigen (HBeAg) following removal of precore-derived signal peptide and the carboxyl terminus. A naturally occurring G1862T mutation upstream of the core AUG affects the bulge of the signal and generates a "forbidden" residue at the ؊3 position of the signal peptide cleavage site. Transfection of this and other mutants into human hepatoma cells failed to prove their inhibition of HBeAg secretion but rather revealed great impairment of genome replication. This replication defect was associated with reduced expression of core protein and could be overcome by a G1899A covariation, or by nonsense or frameshift mutation in the precore region. All these mutations antagonized the G1862T mutation on core protein expression. Cotransfection of the G1862T mutant with a replication-deficient HBV genome that provides core protein in trans also restored genome replication. Consistent with our findings in cell culture, HBV genotype A found in African/Asian patients has T1862 and is associated with much lower viremia titers than the European subgroup of genotype A.The hepatitis B virus (HBV) primarily infects the liver and causes chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma worldwide. It is an enveloped DNA virus with a small double-stranded genome of 3.2 kb. Inside hepatocytes, viral genomic and subgenomic RNAs are transcribed from a covalently closed circular DNA template in the nucleus and exported to the cytoplasm for translation into viral proteins. The core protein assembles into the core particle, packaging both the pregenomic RNA and DNA polymerase. Subsequently, the DNA polymerase synthesizes the negative-strand DNA via reverse transcription from the RNA template, followed by RNA degradation and synthesis of positive-strand DNA. The core particle with the double-stranded DNA genome is enveloped by host-derived lipids and viral envelope proteins and secreted as an infectious virus particle (for a review, see reference 7). Since the 3.5-kb pregenomic RNA is also the mRNA for the expression of both core protein and DNA polymerase, it is the sole component required for genome replication. Consequently, increased transcription of pregenomic RNA will lead to enhanced HBV replication, as exemplified by the naturally occurring core promoter mutants (3,20).The AUG initiator of the core gene (position 1901 to 1903) is located approximately 80 nucleotides (nt) downstream of the 5Ј end of its mRNA, while the initiation codon of polymerase is 400 nt further downstream. Therefore, core pro...

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Section: Discussionsupporting

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Point Mutations Upstream of Hepatitis B Virus Core Gene Affect DNA Replication at the Step of Core Protein Expression

Guarnieri

Kim

Bang

et al. 2006

J Virol

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“…HBV/C has a higher G1762T/G1764A double mutation rate and a lower G1896A mutation rate than does HBV/B (26). A subgenotype of HBV/A, HBV/Aa (17,35), which is distributed in Asia and Africa, has subgenotype-specific substitutions just prior to precore ORF start codons (Kozak sequences), and the mutation causes reduction of HBeAg (2,38).…”

Section: Discussionmentioning

confidence: 99%

Novel Type of Hepatitis B Virus Mutation: Replacement Mutation Involving a Hepatocyte Nuclear Factor 1 Binding Site Tandem Repeat in Chronic Hepatitis B Virus Genotype E

Fujiwara

Tanaka²,

Paulon

et al. 2005

J Virol

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The genetic diversity of hepatitis B virus (HBV) strains has evolved through mutations such as point mutations, deletions or insertions, and recombination. We identified and characterized a novel type of mutation which is a complex of external insertion, deletion, and internal duplication in sequences from one of six patients with chronic hepatitis B virus genotype E (HBV/E). We provisionally named this mutation a "replacement mutation"; the core promoter upstream regulatory sequence/basic core promoter was replaced with a part of the S1 promoter covering the hepatocyte nuclear factor 1 (HNF1) binding site, followed by a tandem repeat of the HNF1 site. A longitudinal analysis of the HBV population over 6 years showed the clonal change from wild-type HBV/E to replacement-mutant type, resulting in a lower hepatitis B (HB) e antigen titer, a high HBV DNA level in serum, and progression of liver fibrosis. In an in vitro study using a replication model, the replacement-mutant HBV showed higher replication levels than the wild-type HBV/E replicon, probably mediated by altered transcription factor binding. Additionally, this HNF1 site replacement mutation was associated with excessive HB nucleocapsid protein expression in hepatocytes, in both in vivo and in vitro studies. This novel mutation may be specific to HBV genotype E, and its prevalence requires further investigation.

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“…HBV subgenotype A1 appears to be associated with low serum HBV DNA levels as well as a low prevalence of serum HBeAg and is implicated in the high incidence of HBV-related HCC in Africa [61]; whereas subgenotype A2 has a higher rate of sustained remission after HBeAg seroconversion and a lower rate of liver-related death than other genotypes during long-term follow-up [62,63]. Sugauchi et al found that positivity of HBeAg is significantly more frequent in carriers of subgenotype B1 than B2 [64].…”

Section: Genotype and Subgenotypementioning

confidence: 99%

Role of viral factors in the natural course and therapy of chronic hepatitis B

Kao

2007

Hepatol Int

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Hepatitis B virus (HBV) infection is a global health problem that causes a wide spectrum of liver disease, including acute or fulminant hepatitis, inactive carrier state, chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The pathogenesis of hepatocyte damage associated with HBV is mainly through immune-mediated mechanisms. On the basis of the virus and host interactions, the natural history of HBV carriers who are infected in early life can be divided into four dynamic phases. The frequency, extent, and severity of hepatitis flares or acute exacerbation in the second immune clearance and/or fourth reactivation phase predict liver disease progression in HBV carriers. In the past decade, hepatitis B viral factors including serum HBV DNA level, genotype, and naturally occurring mutants predictive of clinical outcomes have been identified. The higher the serum HBV DNA level after the immune clearance phase, the higher the incidence of adverse outcomes over time. In addition, high viral load, genotype C, basal core promoter mutation, and pre-S deletion correlate with increased risk of cirrhosis and HCC development. As to the treatment of chronic hepatitis B, patients with high HBV DNA level and genotype C or D infection are shown to have a worse response to interferon therapy. In conclusion, serum HBV DNA level, genotype, and naturally occurring mutants are identified to influence liver disease progression and therapy of chronic hepatitis B. More investigations are needed to clarify the molecular mechanisms of the viral factors involved in the pathogenesis of each stage of liver disease and the response to antiviral treatments.

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A case-control study for differences among hepatitis B virus infections of genotypes A (subtypes Aa and Ae) and D †

Cited by 140 publications

References 49 publications

Point Mutations Upstream of Hepatitis B Virus Core Gene Affect DNA Replication at the Step of Core Protein Expression

Point Mutations Upstream of Hepatitis B Virus Core Gene Affect DNA Replication at the Step of Core Protein Expression

Novel Type of Hepatitis B Virus Mutation: Replacement Mutation Involving a Hepatocyte Nuclear Factor 1 Binding Site Tandem Repeat in Chronic Hepatitis B Virus Genotype E

Role of viral factors in the natural course and therapy of chronic hepatitis B

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