## 3 Control of HDV RNA Editing
### Negative Feedback Regulation of Editing  
HDV must regulate both the rate and the extent of editing at the amber/W site because, as shown in Section 4, levels of viral RNA replication and virion production are sensitive to the kinetics and amount of HDAg-L produced. Moreover, as shown in Figure 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 HDAg-L; such genomes will not be able to replicate. Analysis of the percentage of HDV RNA edited in cells and in virus particles indicates that maximum editing levels are around 30%, and may vary for different genotypes [47,48]. Thus, it appears that HDV controls the ultimate level of editing achieved and may thus ensure continued virus viability.  
Two studies have indicated that editing can be regulated by negative feedback [12,46], but the mechanisms are different. [PERSON] _et al._ showed that, although HDAg-S does not effectively reduce editing, HDAg-L strongly inhibits editing of a non-replicating HDV type 3 RNA [46]. These results initially led to the suggestion that regulation of editing in type 3 involves a negative feedback loop in which HDAg-L, which is produced as a result of editing, directly inhibits editing. In this event, the mechanisms for controlling ultimate editing levels would differ for HDV types 1 and 3 (for type 1 both HDAg-S and HDAg-L inhibit editing of non-replicating RNAs equally well). However, preliminary data from our laboratory indicate that this interpretation must be modified. Although the results indicated that HDAg-L alone is a potent inhibitor of type 3 editing, this protein is never present in cells replicating HDV without HDAg-S. More recent analysis has indicated that mixtures of type 3 HDAg-S and HDAg-L at ratios similar to those found in cells replicating HDV exhibit inhibitory activities similar to HDAg-S (RC, unpublished). Hence, it appears that levels of HDAg-L achieved during replication might not be sufficient to directly affect editing of HDV type 3.  
We currently favor the model proposed by [PERSON] _et al._, who suggested that HDAg-L can indirectly regulate amber/W editing by inhibiting HDV RNA replication [12]. As can be seen in the model of HDV replication (Figure 1), HDAg-L production requires HDV RNA synthesis; thus, inhibition of RNA synthesis as HDAg-L accumulates to inhibitory levels will prevent further HDAg-L production. The [PERSON] model takes this idea one step further, and suggests that editing also requires replication of the RNA. This model is consistent with our proposed model for editing of HDV type 3 RNA - the branched structure required for editing can only be formed following RNA synthesis [13]; thus, once RNA synthesis is inhibited, no additional editing will occur. For HDV type 1, this model depends on the proposal that only newly synthesized antigenomic RNAs can be edited [12]. The mechanism in this case is not yet clearly proven, but it seems likely that it will involve the ability of HDAg to block editing at the HDV type 1 amber/W site by binding the RNA. Perhaps, only newly synthesized HDV type 1 RNA has not yet been bound by HDAg and can therefore be edited by ADAR1.