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J Virol, July 1998, p. 5449-5456, Vol. 72, No. 7
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Transcription of Hepatitis Delta Antigen mRNA
Continues throughout Hepatitis Delta Virus (HDV) Replication: a New
Model of HDV RNA Transcription and Replication
Lucy E.
Modahl1 and
Michael M. C.
Lai1,2,*
Department of Molecular Microbiology and
Immunology1 and
Howard Hughes Medical
Institute,2 University of Southern California
School of Medicine, Los Angeles, California 90033-1054
Received 17 February 1998/Accepted 27 March 1998
Hepatitis delta virus (HDV) replicates by RNA-dependent RNA
synthesis according to a double rolling circle model. Also synthesized during replication is a 0.8-kb, polyadenylated mRNA encoding the hepatitis delta antigen (HDAg). It has been proposed that this mRNA
species represents the initial product of HDV RNA replication; subsequent production of genomic-length HDV RNA relies on suppression of the HDV RNA polyadenylation signal by HDAg. However, this model was
based on studies which required the use of an HDV cDNA copy to initiate
HDV RNA replication in cell culture, thus introducing an artificial
requirement for DNA-dependent RNA synthesis. We have now used an HDV
cDNA-free RNA transfection system and a method that we developed to
detect specifically the mRNA species transcribed from the HDV RNA
template. We established that this polyadenylated mRNA is 0.8 kb in
length and its 5' end begins at nucleotide 1631. Surprisingly, kinetic
studies showed that this mRNA continued to be synthesized even late in
the viral replication cycle and that the mRNA and the genomic-length
RNA increased in parallel, even in the presence of HDAg. Thus, a switch
from production of the HDAg mRNA to the full-length HDV RNA does not
occur in this system, and suppression of the polyadenylation site by
HDAg may not significantly regulate the synthesis of the HDAg mRNA, as previously proposed. These findings reveal novel insights into the
mechanism of HDV RNA replication. A new model of HDV RNA replication and transcription is proposed.
*
Corresponding author. Mailing address: Dept. of MMI,
USC School of Medicine, 2011 Zonal Ave., HMR-503, Los Angeles, CA
90033-1054. Phone: (213) 342-1748. Fax: (213) 342-9555. E-mail:
michlai{at}hsc.usc.edu.
J Virol, July 1998, p. 5449-5456, Vol. 72, No. 7
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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