Other Forms of Delta Protein

While S-HDAg is essential for replication other forms of the protein arise during replication. The best characterized other form is L-HDAg. It arises as a consequence of RNA-editing at a specific site, nucleotide 1012, in one genome numbering scheme (Kuo et al. 1988a). This location corresponds to the middle of the amber termination codon of S-HDAg. The RNA editing is carried out by ADAR-1, an adenosine deaminase acting on RNA (Sect. 4.2).

The L-HDAg contains a single cysteine, located four amino acids from its novel C terminus. This cysteine is isoprenylated in vivo, and plays an essential role in the ability of this L-HDAg to facilitate virus assembly (Chang et al. 1991;

Table 1 Proposed roles of S-HDAg in HDV replication

1. Form an RNP that stabilizes the genome and antigenome (Chao et al. 1991; Lazinski and Taylor 1995)

2. Form an RNP that protects HDV RNAs against ADAR editing (Cheng et al. 2003)

3. Form an RNP that facilitates transport of the HDV genome to the nucleus (Xia etal. 1992)

4. Act as an RNA chaperone to accelerate the HDV ribozyme activities (Huang and Wu 1998; Jeng et al. 1996)

5. Act as a facilitator of processivity during RNA-directed RNA transcription (Yamaguchi et al. 2001)

Glenn et al. 1992). The L-HDAg does not support HDV genome replication and at least under certain conditions, acts as a dominant negative inhibitor of such replication (Chao et al. 1990; Sato et al. 2004).

To consider HDV replication as being associated with just these two forms of HDAg is too simple. One has to factor in the consequences of post-translational modifications, such as phosphorylation, acetylation, methyla-tion, and isoprenylation (see chapter by W.-H Huang et al., this volume). In addition, it would seem that there are other RNA editing sites and there are certainly sites at which transcriptional errors occur (Sect. 4). Some of these sequence changes can lead to S-HDAg with altered sequence and functionality. Thus, once HDV replication is underway, there is a real heterogeneity in the amino acid sequence of those species, some of which will electrophoretically migrate the same as the prototypic S-HDAg or L-HDAg (Gudima et al. 2002). This heterogeneity is particularly true in situations where HDV replication is occurring in the absence of packaging followed by virus release and new rounds of infection; that is, when there is no selection for functional HDAg.

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