Inside a delta virus particle the genomic RNA is bound to molecules of S-HDAg (Bichko et al. 1996; Dingle et al. 1998; Ryu et al. 1993). As discussed later in Sect. 3.1, this protein that is the only one encoded by HDV, exists in two main size classes. The 195-amino acid S-HDAg is essential for HDV replication. During replication RNA editing leads to a change in the amber stop codon of S-HDAg to tryptophan (see chapter by J.L. Casey, this volume). This so-called amber/W mutation, leads to the translation of a protein form that is 19 amino acids longer at the C terminus. The resultant 214 amino acid large delta protein (L-HDAg) is both an inhibitor of replication and is essential, along with the envelope proteins of HBV, for the assembly of new virus particles (Chang et al. 1991; Chao et al. 1990). However, additional findings indicate that it is only when this L-HDAg is isoprenylated that it can function to assist assembly (Glenn et al. 1992) or to act as an inhibitor of replication (Sato et al. 2004).

In natural infections, the assembled HDV particles contain both forms of HDAg in a ribonucleoprotein structure with the HDV genomic RNA (Ryu et al. 1992). In virions there are about 70 molecules of S-HDAg bound per molecule of genomic RNA (Ryu et al. 1993). These interactions are facilitated by an RNA-binding domain that is shared by both forms of HDAg (Lee et al. 1993).

Within a cell undergoing HDV genome replication the majority of the accumulated genomic and antigenomic RNAs exist in complexes with S-HDAg. This has been demonstrated by immunoaffinity procedures using antibody specific for S-HDAg; in contrast, the mRNA for HDAg is not in such a complex (Nie, Chang, Taylor, unpublished). These findings are consistent with earlier reports that in vitro, S-HDAg can specifically recognize the rod-like folding of the genomic and antigenomic RNAs (Chao et al. 1991). A detailed comparison of the stoichiometry of S-HDAg per RNA has yet to be made for the intracellular ribonucleoprotein (RNP) relative to the virion RNP. Also, it will be important to determine the crystal structure of molecules of S-HDAg bound to a segment of HDV rod-like RNA.

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