Hepatitis Delta Virus RNA Encoding the Large Delta Antigen Cannot Sustain Replication due to Rapid Accumulation of Mutations Associated with RNA Editing
AUTOR(ES)
Macnaughton, Thomas B.
FONTE
American Society for Microbiology
RESUMO
Hepatitis delta virus (HDV) contains two RNA species (HDV-S and HDV-L), which encode the small and large forms of hepatitis delta antigens (S- and L-HDAg), respectively. HDV-L RNA is a result of an RNA editing event occurring at an amber/W site of HDV-S RNA. RNA editing must be regulated to prevent premature and excessive accumulation of HDV-L RNA in the viral life cycle. In this study, we used an RNA transfection procedure to study the replication abilities of HDV-L and HDV-S RNA. While HDV-S led to robust RNA replication, HDV-L could not replicate even after 6 days following transfection. The failure of HDV-L to replicate was not due to insufficient amounts of S-HDAg, as identical results were obtained in a cell line that stably overexpresses S-HDAg. Also, it was not due to possible inhibition by L-HDAg, as HDV-S RNA replication was not affected when both HDV-L and HDV-S RNA were cotransfected. Further, when L-HDAg expression from HDV-L RNA was abolished by site-directed mutagenesis, the mutant HDV-L RNA also failed to replicate. Unexpectedly, when the kinetics of RNA replication was examined daily, HDV-L was found to replicate at a low level at the early time points (1 to 2 days posttransfection) but then lose this capability at later time points. Sequence analysis of the replicated HDV-L RNA at day 1 posttransfection showed that it had undergone multiple nucleotide changes, particularly in the region near the putative promoter region of HDV RNA replication. In contrast, very few mutations were found in HDV-S RNA. These results suggest that the editing at the amber/W site triggers a series of additional mutations which rapidly reduce the replication efficiency of the resultant HDV genome and thus help regulate the amount of HDV-L RNA in infected cells. They also explain why L-HDAg is not produced early in HDV infection, despite the fact that HDV-L RNA is present in the virion.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=254293Documentos Relacionados
- Large Hepatitis Delta Antigen Is Not a Suppressor of Hepatitis Delta Virus RNA Synthesis once RNA Replication Is Established
- Hepatitis Delta Virus Replication Generates Complexes of Large Hepatitis Delta Antigen and Antigenomic RNA That Affiliate with and Alter Nuclear Domain 10
- Genotype-Specific Complementation of Hepatitis Delta Virus RNA Replication by Hepatitis Delta Antigen
- Differential Inhibition of RNA Editing in Hepatitis Delta Virus Genotype III by the Short and Long Forms of Hepatitis Delta Antigen
- By Inhibiting Replication, the Large Hepatitis Delta Antigen Can Indirectly Regulate Amber/W Editing and Its Own Expression