Action of inhibitors on accumulation of processed hepatitis delta virus RNAs.
Hepatitis delta virus (HDV) replication involves processing and accumulation of three RNA species: the genome, its exact complement (the antigenome), and a polyadenylated mRNA that acts as a template for the small delta antigen (deltaAg), the only protein of HDV and essential for genome replication. In a recently reported experimental system, addition of tetracycline induced synthesis of a DNA-directed source of deltaAg, producing within 24 h a significant increase in accumulation of newly transcribed and processed HDV RNAs. This induction was used here to study the action of various inhibitors on accumulation. For example, potent and HDV-specific inhibition, in the absence of detected host toxicity, could be obtained with ribavirin, mycophenolic acid, and viramidine. An interpretation is that these inhibitors reduced the available GTP pool, leading to a specific inhibition of the synthesis and accumulation of HDV RNA-directed RNA species. In contrast, no inhibition was observed with L-FMAU (2'-fluoro-5-methyl-beta-L-arabinofuranosyl-uridine), alpha interferon, or pegylated alpha interferon. After modifications to the experimental system, it was also possible to examine the effects of three known host RNA polymerase inhibitors on HDV genome replication: amanitin, 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB), and actinomycin. Of most interest, amanitin at low doses blocked accumulation of HDV RNA-directed mRNA but had less effect on HDV genomic and antigenomic RNAs. Additional experiments indicated that this apparent resistance to amanitin inhibition of genomic and antigenomic RNA relative to mRNA may not reflect a difference in the transcribing polymerase but rather relative differences in the processing and stabilization of nascent RNA transcripts.
Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA.
Jinhong
J
Chang
Xingcao
X
Nie
Severin
S
Gudima
John
J
Taylor
D000546:Amanitins / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D003609:Dactinomycin / Q000494:pharmacology; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016679:Genome, Viral; D003698:Hepatitis Delta Virus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009173:Mycophenolic Acid / Q000494:pharmacology*; D026723:Polyadenylation; D012333:RNA, Messenger / Q000096:biosynthesis; D012367:RNA, Viral / Q000096:biosynthesis*; D012254:Ribavirin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014779:Virus Replication
D000546:Amanitins; D000998:Antiviral Agents; D012333:RNA, Messenger; D012367:RNA, Viral; D003609:Dactinomycin; D012254:Ribavirin; D004004:Dichlororibofuranosylbenzimidazole; D009173:Mycophenolic Acid; C026956:taribavirin