Type, prevalence, and significance of core promoter/enhancer II mutations in hepatitis B viruses from immunosuppressed patients with severe liver disease

Günther, Stephan; Piwon, Nils; Iwanska, Alicja; Schilling, R; Meisel, Helga; Will, Hans

doi:10.1128/jvi.70.12.8318-8331.1996

Cited by 128 publications

(99 citation statements)

References 52 publications

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“…After isolation of DNA from the serum complete HBV genomes were amplified by a full-length polymerase chain reaction (PCR) by using the same conditions as described previously. 20,21 Afterwards PCR products were purified with the Qiagen PCR purification kit (Qiagen, Hilden, Germany) and used for transfection.…”

Section: Methodsmentioning

confidence: 99%

A dominant hepatitis B virus population defective in virus secretion because of several S-gene mutations from a patient with fulminant hepatitis

et al. 2001

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There is increasing evidence that certain pathogenic hepatitis B virus (HBV) variants may play a role in the pathogenesis of fulminant hepatitis (FHB). Recently, we isolated from a patient with fulminant recurrent hepatitis B after liver transplantation variants with enhanced replication competence and a possible defect in viral particle secretion. Both viral features may have contributed to the severity of the disease. The aim of this study was to prove the secretion defect of these variants, to analyze the consequences, and to identify the responsible viral mutations. The variant genomes and appropriate wild-type/variant hybrid genomes were functionally characterized after transfection in human hepatoma cells. Two cloned genomes and the polymerase chain reaction (PCR)-amplified mixture of full-length genomes showed a block in viral particle secretion. This was caused by a combination of amino acid changes in the Sprotein including the mutation G145R frequently emerging after hyperimmunoglobulin treatment. The mutations induced retention of the surface proteins in an endoplasmic reticulum (ER)-like compartment, but no intracellular accumulation. These data provide evidence for the in vivo existence of a dominant HBV population with a severe defect in The occurrence of hepatitis B virus (HBV) variants as minor or major viral populations in infected patients with fulminant, acute, and chronic hepatitis B was amply documented in the past. 1-5 HBV variants can differ from wild-type virus (WT) both in the DNA and viral protein sequences. Sequence variability and mutations were found in regulatory regions as well as in structural and nonstructural proteins. There is increasing evidence for a role of specific hepadnaviral variants in establishing chronic infection, virus/host cell interaction, and hepatopathogenesis. 4,5 In addition, several epidemic outbreaks of fulminant hepatitis B infections, which could be traced back to one chronically infected carrier, argue for an impact of viral variants in the pathogenesis of fulminant hepatitis (FHB). 6-9 Furthermore, it was shown that viral strains isolated from patients with FHB are particularly pathogenic for chimpanzees. 10 Three animals that were infected with serum of a child who transmitted FHB to 2 pediatricians developed severe hepatitis with unusually high transaminases for these animals. Based on the hypothesis that certain pathogenic HBV strains may cause or contribute to FHB several studies tried to identify structural characteristics of viral variants of these patients by determining the DNA and amino acid sequences of certain regions or the complete HBV genomes. 11-14 These experiments revealed that certain mutations, such as the precore stop codon mutation A-1896 and the core promoter mutations T-1762 and A-1764 occur more frequently in patients with FHB compared with chronic carriers, but no mutation specific for this disease course could be identified. However, this does not exclude a role of HBV variants in the pathogenesis of FHB because several differen...

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Section: Methodsmentioning

confidence: 99%

A dominant hepatitis B virus population defective in virus secretion because of several S-gene mutations from a patient with fulminant hepatitis

et al. 2001

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“…The core antigen-coding region appears to be stable prior to seroconversion, but mutations are rapidly selected as a consequence of the anticore immune response (13,334). Fitness enhancement of HBV can follow after mutations in the basal core promoter that increase binding of liver-specific transcription factors are selected, leading to enhanced viral replication (335,792).…”

Section: Hepatitis B Virusmentioning

confidence: 99%

Viral Quasispecies Evolution

Domingo

Sheldon

Perales

2012

Microbiol Mol Biol Rev

847

880

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SUMMARY Evolution of RNA viruses occurs through disequilibria of collections of closely related mutant spectra or mutant clouds termed viral quasispecies. Here we review the origin of the quasispecies concept and some biological implications of quasispecies dynamics. Two main aspects are addressed: (i) mutant clouds as reservoirs of phenotypic variants for virus adaptability and (ii) the internal interactions that are established within mutant spectra that render a virus ensemble the unit of selection. The understanding of viruses as quasispecies has led to new antiviral designs, such as lethal mutagenesis, whose aim is to drive viruses toward low fitness values with limited chances of fitness recovery. The impact of quasispecies for three salient human pathogens, human immunodeficiency virus and the hepatitis B and C viruses, is reviewed, with emphasis on antiviral treatment strategies. Finally, extensions of quasispecies to nonviral systems are briefly mentioned to emphasize the broad applicability of quasispecies theory.

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“…Recent studies also have shown that core promoter mutations commonly are present in patients with severe or FH B. [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.…”

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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Type, prevalence, and significance of core promoter/enhancer II mutations in hepatitis B viruses from immunosuppressed patients with severe liver disease

Cited by 128 publications

References 52 publications

A dominant hepatitis B virus population defective in virus secretion because of several S-gene mutations from a patient with fulminant hepatitis

A dominant hepatitis B virus population defective in virus secretion because of several S-gene mutations from a patient with fulminant hepatitis

Viral Quasispecies Evolution

Exploring the biological basis of hepatitis B e antigen in hepatitis B virus infection

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