Effects of a naturally occurring mutation in the hepatitis B virus basal core promoter on precore gene expression and viral replication

Buckwold, Victor E.; Xu, Zhenming; Chen, M.; Yen, T. S. Benedict; Ou, Jing-Hsiung

doi:10.1128/jvi.70.9.5845-5851.1996

Cited by 431 publications

(259 citation statements)

References 43 publications

(51 reference statements)

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“…Mutations in the core promoter and precore region have been shown to decrease or abolish HBeAg production. 10,11 The polymerase protein functions as a reverse transcriptase as well as a DNA polymerase. The X protein is a potent transactivator and may play a role in hepatocarcinogenesis.…”

Section: Hepatitis B Virusmentioning

confidence: 99%

Chronic hepatitis B

2001

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PREAMBLEThese guidelines have been written to assist physicians and other health care providers in the recognition, diagnosis, and management of patients chronically infected with the hepatitis B virus (HBV). They are intended to suggest preferable approaches to the clinical management of chronic hepatitis B. The recommendations are flexible and are not intended as the only acceptable approach to management and treatment. As the appropriate course of treatment will vary in light of the relevant facts and circumstances surrounding each individual patient with chronic hepatitis B, guidelines are not intended to define the applicable standard of medical care and may be updated periodically as new information becomes available.These guidelines were developed under the auspices of, and approved by, the Practice Guidelines Committee of the American Association for the Study of Liver Diseases. They should be taken as guidelines and not "standards of care." Data used to support the recommendations made were obtained by a literature search of peer-reviewed articles concerning the natural history, diagnosis, and treatment of chronic hepatitis B. In addition, the proceedings of a recent National Institutes of Health workshop on the "Management of Hepatitis B" were considered in the development of these guidelines. 1 The strength of each recommendation is categorized based on the quality of evidence in the literature according to the rating system indicated in Table 1. 2

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Section: Hepatitis B Virusmentioning

confidence: 99%

Chronic hepatitis B

2001

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“…[41][42][43][44] Some of these mutations confer enhanced replication. [45][46][47][48][49][50] Additionally, mutations in the surface gene have been implicated in some cases of FH B. 51 Therefore, a number of viral mutations and/or host factors likely are involved in the pathogenesis of FH.…”

Section: Clinical-pathologic Features Of Hbeag-negative Variantsmentioning

confidence: 99%

Exploring the Biological Basis of Hepatitis B E Antigen in Hepatitis B Virus Infection

2003

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The function of the hepatitis B e antigen (HBeAg) is largely unknown because it is not required for viral assembly, replication, or infection. In this report we chronicle clinical and experimental studies in an attempt to understand the role of HBeAg in natural infection. H epatitis B virus (HBV) infects more than 300 million people and is a major cause of acute and chronic liver disease in the world. HBV infection has been linked unequivocally to the development of hepatocellular carcinoma. Since the discovery of HBV nearly 3 decades ago, great strides have been made not only in characterizing the molecular biology and immunology of HBV infection, but also in defining the mechanisms of pathogenesis in hepatitis B. However, a few areas of HBV remain highly controversial and/or largely undefined. The biologic function of hepatitis B e antigen (HBeAg) has been such an area of intense research. HBeAg is an accessory protein of HBV, not required for viral replication but important for natural infection in vivo. In this report, we discuss the current state of knowledge and highlight the recent advances in understanding this intriguing gene product, mostly in the context of natural HBV infection and its associated disease.

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“…The BCP mutations when engineered into an infectious clone were associated with an increase in virion production. 34,35 Other mutations that created novel transcription factor binding sites in promoter or enhancer regions also had a high replication yield phenotype. 30 However, other groups have shown that while the BCP mutations were associated with reduced HBeAg production, there was no significant effect on the amount of intracellular preS1/PreS2/S proteins or PreS/S messenger RNA transcripts.…”

Section: Functional Studies: Phenotype Assessment and Replication Fitmentioning

confidence: 99%

Hepatitis B Virus Mutants and Fulminant Hepatitis B: Fitness Plus Phenotype

Bartholomeusz

2001

Hepatology

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The human hepatitis B virus (HBV) is the smallest known double-stranded DNA virus of man that replicates its genome through a novel mechanism of reverse transcription using the RNA-replicative intermediate and the viral pregenomic RNA. 1 Viral pregenomic RNA is synthesized from molecules of covalently closed circular (ccc) DNA, the major transcriptional template of the virus, functioning as a viral minichromosome within the nucleus of infected cells. 2 The reverse transcriptase of HBV lacks a conventional proofreading function, which is found in higher-order polymerases and, not surprisingly then, HBV exhibits a mutation rate more than 10-fold higher than other DNA viruses. The rates for nucleotide substitutions vary depending on the stage of disease. The natural evolutionary rate for the HBV genome in chronic hepatitis B is approximately 1.4 to 3.2 ϫ 10 Ϫ5 substitutions/site/year, 3 whereas in the liver transplantation setting, it is almost 100-fold higher. 4 Longitudinal studies have shown that these HBV mutations are not distributed evenly over the entire genome but rather tend to cluster into mutational patterns in particular parts of the viral DNA; in particular, the basal core promoter (BCP), the precore region and the "a" determinant of the viral envelope. 5 Importantly, the type and number of mutations that accumulate in the HBV genome over time have been shown to be a marker of the duration and/or severity of the liver disease, or the type and intensity of the immune response. 5 The outcome of HBV infection depends on the interplay between the virus, the hepatocyte, and the host's immune response. 6 Under normal circumstances, HBV is not cytopathic and liver damage is the result of the host's immune response targeting infected hepatocytes. However, during special or unusual circumstances, HBV appears to be directly cytopathic for hepatocytes often causing unique histopathologic conditions such as fibrosing cholestatic hepatitis, which, before the advent of specific antiviral therapy, 7 was invariably fatal. The molecular virologic and cellular basis for fulminant hepatitis B (FHB) has been the focus of intensive investigation, but to date the results have been controversial. In the report by Kalinina et al. in this issue of HEPATOLOGY, the investigators, have provided the first evidence, using in vitro functional studies that mutations in the S gene of the HBV isolated at the time of FHB had caused a severe defect in viral particle secretion. Earlier studies from this group had shown that the infectious clones from the same samples exhibited enhanced replication levels. 8 The enhanced replication and the severe defect in viral particle secretion most likely contributed to the fulminant clinical course of recurrent HBV infection posttransplantation. The patient was also hepatitis B e antigen (HBeAg) negative. REGULATION OF HEPADNAVIRAL cccDNA: ROLE OF THE VIRAL ENVELOPEVirus persistence in infected cells during chronic infection depends on the maintenance of the HBV cccDNA pool. 9 This pool of transcript...

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Effects of a naturally occurring mutation in the hepatitis B virus basal core promoter on precore gene expression and viral replication

Cited by 431 publications

References 43 publications

Chronic hepatitis B

Chronic hepatitis B

Exploring the Biological Basis of Hepatitis B E Antigen in Hepatitis B Virus Infection

Hepatitis B Virus Mutants and Fulminant Hepatitis B: Fitness Plus Phenotype

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