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Journal of Virology, August 2000, p. 7375-7380, Vol. 74, No. 16
Howard Hughes Medical
Institute2 and Department of Molecular
Microbiology and Immunology,1 University of
Southern California School of Medicine, Los Angeles, California 90033
Received 3 February 2000/Accepted 16 May 2000
Hepatitis delta virus (HDV) contains two types of hepatitis delta
antigens (HDAg) in the virion. The small form (S-HDAg) is required for
HDV RNA replication, whereas the large form (L-HDAg) potently inhibits
it by a dominant-negative inhibitory mechanism. The sequential
appearance of these two forms in the infected cells regulates HDV RNA
synthesis during the viral life cycle. However, the presence of almost
equal amounts of S-HDAg and L-HDAg in the virion raised a puzzling
question concerning how HDV can escape the inhibitory effects of L-HDAg
and initiate RNA replication after infection. In this study, we
examined the inhibitory effects of L-HDAg on the synthesis of various
HDV RNA species. Using an HDV RNA-based transfection approach devoid of
any artificial DNA intermediates, we showed that a small amount of
L-HDAg is sufficient to inhibit HDV genomic RNA synthesis from the
antigenomic RNA template. However, the synthesis of antigenomic RNA,
including both the 1.7-kb HDV RNA and the 0.8-kb HDAg mRNA, from the
genomic-sense RNA was surprisingly resistant to inhibition by L-HDAg.
The synthesis of these RNAs was inhibited only when L-HDAg was in vast
excess over S-HDAg. These results explain why HDV genomic RNA can
initiate replication after infection even though the incoming viral
genome is complexed with equal amounts of L-HDAg and S-HDAg. These
results also suggest that the mechanisms of synthesis of genomic versus antigenomic RNA are different. This study thus resolves a puzzling question about the early events of the HDV life cycle.
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
The Large Delta Antigen of Hepatitis Delta Virus
Potently Inhibits Genomic but Not Antigenomic RNA Synthesis: a
Mechanism Enabling Initiation of Viral Replication
*
Corresponding author. Mailing address: Department of
Molecular Microbiology and Immunology, University of Southern
California School of Medicine, 2011 Zonal Ave., HMR 401, Los Angeles,
CA 90033. Phone: (323) 442-1748. Fax: (323) 342-9555. E-mail:
michlai{at}hsc.usc.edu.
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