Control of ADAR1 editing of hepatitis delta virus RNAs

Hepatitis delta virus (HDV) uses ADAR1 editing of the viral antigenome RNA to switch from viral RNA replication to packaging. At early times in the replication cycle, the virus produces the protein HDAg-S, which is required for RNA synthesis; at later times, as result of editing at the amber/W site, the virus produces HDAg-L, which is required for packaging, but inhibits further RNA synthesis as levels increase. Control of editing during the replication cycle is essential for the virus and is multifaceted. Both the rate at which amber/W site editing occurs and the ultimate amount of editing are restricted; moreover, despite the nearly double stranded character of the viral RNA, efficient editing is restricted to the amber/W site. The mechanisms used by the virus for controlling editing operate at several levels, and range from molecular interactions to procedural. They include the placement of editing in the HDV replication cycle, RNA structural dynamics, and interactions of both ADAR1 and HDAg with specific structural features of the RNA. That HDV genotypes 1 and 3 use different RNA structural features for editing and control the process in ways related to these features underscores the critical roles of editing and its control in HDV replication. This review will cover the mechanisms of editing at the amber/W site and the means by which the virus controls it in these two genotypes.