Differences in Viral Editing Packaging and Replication Efficiencies Between Genotypes I and II HDV

There are several functional domains of HDAg that are closely associated with viral replication or packaging. Mutations or alteration of amino acids within these domains may influence functions associated with viral replication or packaging. Of these functional domains, the 19 amino acids at the carboxyl-end of the L-HDAg show the greatest divergences (70%-80%) between genotypes I and II (Table 2) [2-4,17-19]. It is reasonable to consider that viral packaging efficiencies may vary greatly between these two genotypes. Hsu et al. reported that viral packaging efficiencies of genotype I HDV isolates are usually higher than those of the genotype II. The difference in packaging efficiencies may be 50-fold or greater. Viral packaging efficiencies vary not only between genotypes I and II, but also among HDV isolates of the same genotype [38]. Isoprenylation is essential for the L-HDAg to interact with HBsAg and the subsequent packaging of HDV virions [40]. Isoprenylation increases hydrophobicity of L-HDAg and facilitates the interaction between L-large HDAg and the envelope proteins composed of HBsAg and membrane lipids [41]. The 11 hydrophobic residues (including proline) of the 19 aa of the genotype I HDV may further increase the interactions compared to only nine hydrophobic residues in the same region of the genotype II. Segment swapping experiments of the L-HDAg indicate that the 19 aa at the carboxyl-end seem to be the most important determinant for viral packaging efficiencies [38]. However, amino acids outside the carboxyl-end 19 residues may also influence packaging efficiency.

Synthesis of L-HDAg requires editing at adenosine 1012 (Amber/W site) of the antigenomic HDV RNA [42-44]. The editing efficiencies of the genotype I HDV are also higher than those of genotype II [38]. Genotype I HDV isolates usually have a unique base-pairing structure required for maximal editing [44] in which nucleotides 1008-1016 are paired with nucleotides 576584 in the predicted rod structure. The pairing is relatively stronger, because there are base pairs on each side of the editing site [26, 44]. Disruption of the 1009A/583U pairing markedly reduces the editing efficiency of 1012A. However, the nucleotide sequences surrounding the editing area are different in genotype II HDV isolates which result in no pairings of 1009A/583U and 1008U/584U and a lower RNA editing efficiency [26, 38]. Recently, Jayan and Casey reported that the conserved RNA secondary structure around the HDV genotype I amber/W site has been selected not for the highest editing efficiency but for optimal viral replication and secretion [45]. In a short report the replication of a genotype I HDV isolate from Italy is 100 fold-higher than that a genotype II HDV from Taiwan [46]. More isolates from each genotype are needed to confirm the difference in viral replication efficiencies between genotypes I and II.

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