## 1 Introduction  
Hepatitis delta virus (HDV) is a subviral human pathogen that increases the severity of acute and chronic hepatitis in those infected with its helper, hepatitis B virus [1]. HDV is similar to viroids in several respects: (i) the genome is a single stranded circular RNA that can form an unbranched rod structure; (ii) the RNA genome is replicated by host RNA polymerase; and (iii) replication involves a rolling circle mechanism requiring autocatalytic cleavage of the RNA by an internal ribozyme. Moreover, for both HDV and viroids, multiple RNA structural features play essential roles in the replication process. HDV differs from viroids in that the genome is larger (\(\sim\)1,700 nt) and encodes a protein, hepatitis delta antigen (HDAg). HDAg serves at least two critical functions in HDV infection: participation in replication of the RNA genome, and packaging of the viral RNA with the envelope protein of hepatitis B virus. These two functions depend on two forms of HDAg, HDAg-S and HDAg-L, that differ by the presence of an additional 19-20 aa at the _C_-terminus of HDAg-L. The 195 aa short form (HDAg-S) is required for RNA replication; the 214 aa long form (HDAg-L) is not only required for RNA packaging, but also inhibits replication [2-6]. Infectious virus encodes HDAg-S, which is the only form of HDAg produced initially. HDAg-L is produced as a result of RNA editing by the host RNA adenosine deaminase ADAR [7-9]. During replication, in a limited fraction of the antigenomic RNA, this enzyme deaminates the adenosine in the amber stop codon of the HDAg gene to inosine (Figure 1). Figure 1: The role of RNA editing in HDV replication. Replication begins with the production of the mRNA for HDAg and the antigenome (_left_). The mRNA produced initially contains an amber stop codon and produces the 195 aa form of HDAg, HDAg-S, which is required for RNA replication. The orientation of the genome (blue) in this schematic is such that the open reading frame of HDAg, which is translated from an antigenomic sense mRNA (red), proceeds from left to right. During the course of replication, in a fraction of the antigenomic RNAs, the adenosine in the amber stop codon in the antigenome (red) is deaminated to inosine by the host RNA editing enzyme ADAR1 (bottom). Upon subsequent RNA replication, the inosine is transcribed as though it were G; as a result, the mRNA produced contains a tryptophan (W) codon instead of the amber stop codon and an additional 19-20 codons are translated to yield HDAg-L, which is required for virion packaging and inhibits replication. Because editing changes the amber stop codon to a tryptophan codon the editing site (denoted by an asterisk) is referred to as the amber/W site. Because inosine base pairs preferentially with C rather than U, upon subsequent replication and transcription, the amber stop codon in the hepatitis delta antigen (HDAg) open reading frame is changed to a tryptophan codon, the reading frame is extended by 19 or 20 codons and HDAg-L is produced. Thus, HDV uses the host RNA editing activity to switch the mode of replication from RNA synthesis to packaging. From the scheme depicted in Figure 1 it is clear that editing plays a central role in the HDV replication cycle. Because HDAg-L is a limiting factor for virus production, insufficient editing reduces virus output [7,10]. Conversely, excessive or premature editing strongly diminishes viral RNA accumulation and, as a result, also decreases virus output [10-12]. Moreover, it is important to note that, unlike mRNA and miRNA substrates for RNA adenosine deamination, HDV mRNA is not edited directly. Rather, editing occurs on the antigenome, which is a replication intermediate. Thus, edited genomes and antigenomes accumulate during the course of replication. Because edited genomes are also packaged into virions, excessive editing reduces the infectivity of viral progeny. From this discussion, it is clear that optimal production of infectious virus requires control of editing.