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Functional analysis of complex hepatitis B virus variants associated with development of liver cirrhosis

Official URL:https://doi.org/10.1053/j.gastro.2006.07.008
PubMed:View item in PubMed
Creators Name:Maerschenz, S. and Endres, A.S. and Brinckmann, A. and Heise, T. and Kristiansen, G. and Nuernberg, P. and Krueger, D.H. and Guenther, S. and Meisel, H.
Journal Title:Gastroenterology
Journal Abbreviation:Gastroenterology
Volume:131
Number:3
Page Range:765-780
Date:September 2006
Keywords:Chronic Hepatitis B, Enzyme-Linked Immunosorbent Assay, Genetic Transcription, Hepatitis B e Antigens, Hepatitis B virus, Immunohistochemistry, Liver Cirrhosis, Mutation, Northern Blotting, Phenotype, Retrospective Studies, Reverse Transcriptase Polymerase Chain Reaction, Southern Blotting, Viral Genome, Viral RNA, Virus Replication
Abstract:BACKGROUND & AIMS: Development of cirrhosis in renal transplant recipients with chronic hepatitis B is associated with the accumulation of complex hepatitis B virus (HBV) variants carrying deletions in the C gene and/or preS region and deletions/insertions in the core promoter. Here, we characterized for the first time the phenotype of these complex HBV variants. METHODS: Representative full-length genomes of the HBV variants that were isolated and cloned from serum and liver of an immunosuppressed renal transplant recipient before and during end-stage liver disease were transfected into the human hepatoma cell line HuH7 and functionally analyzed. RESULTS: The variant genomes showed considerably reduced levels of precore and surface messenger RNA (mRNA) and of the major spliced pregenomic RNA, an increased level of pregenomic RNA, and a partial or complete defect in hepatitis B e antigen, core, and surface protein expression/secretion. Very low amounts of variant core protein with internal deletion were detectable. Reduced hepatitis B surface antigen secretion of some variants correlated with aberrant localization of surface proteins in endoplasmic reticulum. Despite the defects in viral protein expression, enhanced replication and enrichment in competition to wild-type HBV were observed. Enhanced reverse transcription and possibly increased levels of pregenomic RNA seem to be responsible for this effect. CONCLUSIONS: Development of cirrhosis is associated with accumulation of complex variants, which exhibit a drastically altered phenotype combining enhanced replication with defects in protein expression. This phenotype appears to be based on the major mutations in the core promoter and C gene but is considerably influenced by additional mutations throughout the genome.
ISSN:0016-5085
Publisher:Elsevier (The Netherlands)
Item Type:Article

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