Regulation of Editing Levels

HDV must regulate both the rate and the extent of editing at the amber/W site because, as shown in Sect. 4, levels of viral RNA replication and virion production are sensitive to the kinetics and amount of L-HDAg produced. Moreover, as shown in Fig. 1, editing occurs not on the mRNA, but on the antigenome, which is a replication intermediate. Hence, HDV RNA editing levels within an infected cell at any given time are the result of the accumulation of all editing events within that cell up to that time, and the percentage of antigenomes containing the UGG codon (and genomes with ACC at the corresponding positions) increases with time. The cost of this mechanism to the virus is that a fraction of viral particles contain genomes that encode L-HDAg; such genomes cannot replicate (Glenn and White 1991). Thus, HDV must control the level of editing in order to ensure viability. HDV does not appear to regulate editing by affecting ADAR1 expression because ADAR1

levels are unaffected by HDV replication (Wong and Lazinski 2002). Control mechanisms for editing rely on several viral components and functions, including: RNA structure, HDAg, and viral RNA replication. These mechanisms vary among genotypes, at least for genotypes I and III.

Some of the control mechanisms may be described as passive, in that they are not affected by (or responsive to) the level of editing. This category includes the secondary structure of the RNA around the amber/W site. As mentioned in Sect. 3.1, the disruptions in base-pairing 3' of the amber/W site in HDV genotype I create a suboptimal substrate for editing. Mutations that increase base-pairing in this region increase editing, but severely reduce replication and virion production (Jayan and Casey 2005; Sato et al. 2004). It is not yet known whether the structures in the vicinity of the amber/W sites of other genotypes are also suboptimal. One potential dilemma for the virus that is posed by using a suboptimal structure to limit editing efficiency is that the specificity of editing is likely to be compromised because the specificity is determined by the ratio of the efficiency of editing at the amber/W site to the efficiency of editing at other 'non-specific' sites. The danger for the virus of nonspecific editing is the production of additional genomes defective for replication, or even the creation of dominant negative S-HDAg mutants (Jayan and Casey 2002a). Thus, there maybe limits as to how much amber/W editing can be restricted by using suboptimal structures. HDV does appear to have a mechanism for minimizing the effects of editing at nonamber/W sites: in one study of HDV replicating in transfected cells, all nonamber/W changes that occurred during replication were found on genomes that were also edited at the amber/W site (Polson et al. 1998).

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