Detection and significance of a G1862T variant of hepatitis B virus in Chinese patients with fulminant hepatitis

Hou, Jinlin; Yao, Lin; Waters, Jennifer A.; Wang, Zhanhui; Jia, Min; Liao, Huiyu; Jiang, Jiaji; Chen, Jinjun; Luo, Kun; Karayiannis, Peter

doi:10.1099/0022-1317-83-9-2291

Cited by 41 publications

(40 citation statements)

References 59 publications

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“…In our study, we focused on the differences between acute, chronic and 'fulminant' infection and we found no association with mutations known to modify HBeAg formation and any of these disease states. This suggests that the presence or absence of HBeAg may not impact upon the initial outcome of exposure to HBV although it is clear from previous studies that it does have a major impact on the further development of chronic infection (Lindh et al, 1996;Tsubota et al, 1998;Hou et al, 2002). The fact that we did not detect G1896A as a candidate mutation should not be interpreted as a failure of our methodology.…”

Section: Discussionmentioning

confidence: 72%

“…This error prone replication strategy leads to a high rate of mutation within the virus, such that the virus constantly evolves both within an individual and a population (Ganem, 1996;Hannoun et al, 2000). Studies of the sequence of HBV in different populations have led to the classification of the virus into a number of different genotypes (labelled alphabetically A-H) (Kramvis and Kew, 2005) and some genotypes may be associated with different disease outcomes and different therapeutic responses (Mayerat et al, 1999;Kao et al, 2000;Hou et al, 2002;Kao, 2002;KiddLjunggren et al, 2002;Fung and Lok, 2004;Jazayeri et al, 2004;Schaefer, 2005). Within individuals who are chronically infected with the virus there is evidence of on-going mutation, with substitution rates as high as 4.2 Â 10 À5 nucleotide substitutions per site per year (Fares and Holmes, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Genome-wide characterisation of Hepatitis B mutations involved in clinical outcome

et al. 2006

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Infection with the hepatitis B virus (HBV) leads to different disease outcomes, which can be broadly divided into three categories: acute mild infection, 'fulminant' and chronic hepatitis (long-term persistent form of the infection). The factors that influence the development of these different disease states are poorly understood and may include viral polymorphisms. To investigate this possibility, we analysed 116 published complete HBV genomes for which we knew disease outcome and had access to associated information on patients (age, sex and geographic origin). Our best statistical model correctly classified 72% of the cases and retained age and sex of the patient, as well as 29 candidate mutations. With the exception of one mutation in the X gene, all were located in the viral polymerase, suggesting this gene plays a critical role in clinical outcome. Our results highlight the importance of the genetics of HBV strains in the evolution of the disease and demonstrate that disease outcome can be predicted to a surprisingly large extent with a limited number of host and viral factors.

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Section: Discussionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Genome-wide characterisation of Hepatitis B mutations involved in clinical outcome

et al. 2006

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“…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%

“…The G1862T mutant of genotype B has been implicated in several cases of fulminant hepatitis in China (8). Interestingly, all such isolates harbored the G1899A mutation but no G1896A nonsense mutation or core promoter mutations (8). Since enhanced replication of the HBV genome is considered critical in the induction of fulminant hepatitis (3), the presence of the G1899A mutation in such strains may not be a mere coincidence.…”

Section: Discussionmentioning

confidence: 99%

“…We found that the G1899A mutation largely relieves the inhibitory effect of the G1862T mutation on genome replication, as a consequence of restored core protein expression. The G1862T mutant of genotype B has been implicated in several cases of fulminant hepatitis in China (8). Interestingly, all such isolates harbored the G1899A mutation but no G1896A nonsense mutation or core promoter mutations (8).…”

Section: Discussionmentioning

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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Molecular Variations in the Core Promoter, Precore and Core Regions of Hepatitis B Virus, and their Clinical Significance

Karayiannis¹,

Carman

Thomas

2005

Viral Hepatitis

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Detection and significance of a G1862T variant of hepatitis B virus in Chinese patients with fulminant hepatitis

Cited by 41 publications

References 59 publications

Genome-wide characterisation of Hepatitis B mutations involved in clinical outcome

Genome-wide characterisation of Hepatitis B mutations involved in clinical outcome

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

Molecular Variations in the Core Promoter, Precore and Core Regions of Hepatitis B Virus, and their Clinical Significance

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