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Research Article Free access | 10.1172/JCI119037

Two core promotor mutations identified in a hepatitis B virus strain associated with fulminant hepatitis result in enhanced viral replication.

T F Baumert, S A Rogers, K Hasegawa, and T J Liang

Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.

Find articles by Baumert, T. in: PubMed | Google Scholar

Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.

Find articles by Rogers, S. in: PubMed | Google Scholar

Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.

Find articles by Hasegawa, K. in: PubMed | Google Scholar

Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.

Find articles by Liang, T. in: PubMed | Google Scholar

Published November 15, 1996 - More info

Published in Volume 98, Issue 10 on November 15, 1996
J Clin Invest. 1996;98(10):2268–2276. https://doi.org/10.1172/JCI119037.
© 1996 The American Society for Clinical Investigation
Published November 15, 1996 - Version history
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Abstract

Viral mutations have been implicated in alteration of the biological phenotype of hepatitis B virus (HBV). We recently cloned and sequenced the viral genome of an HBV strain associated with an outbreak of fulminant hepatitis (FH strain). The FH strain contained numerous mutations in all genomic regions and was functionally characterized by a more efficient encapsidation of pregenomic RNA leading to highly enhanced replication. To define the responsible mutation(s) for the enhanced replication, we introduced individual mutations of the FH strain into a wild-type construct by oligonucleotide-directed mutagenesis. Analysis of viral replication showed that two adjacent mutations in the HBV core promotor (C to T at nucleotide 1768 and T to A at nucleotide 1770) led to high level replication. Similar to the FH strain, this mutant displayed the phenotype of enhanced encapsidation of pregenomic RNA. Functional studies in an encapsidation assay demonstrated that the identified mutations resulted in a minor increase of pregenomic RNA transcription (two- to threefold) and a major transcription-independent enhancement (> 10-fold) of viral encapsidation. Our results demonstrate that the two adjacent mutations in the HBV core promotor region are responsible for the enhanced replication of the FH strain. These two mutations, outside the previously described encapsidation signal, core, and polymerase polypeptides, appeared to affect a novel genetic element involved in viral encapsidation.

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