Effects of HDAg

HDV genotype I uses an additional mechanism to slow down editing early in the replication cycle. For this genotype, S-HDAg, which is known to bind HDV RNA (Chang et al. 1988), is a strong inhibitor of editing at the amber/W site. While editing on replicating RNA 2-3 days post-transfection is nearly undetectable, up to 40% of nonreplicating RNAs produced in transfected cells in the absence of HDAg are edited. However, co-transfection of an S-HDAg expression construct leads to markedly reduced levels of editing on nonreplicating RNAs (Polson et al. 1998). The levels of S-HDAg required for this inhibition are similar to those seen in cells replicating HDV RNA. Thus, it appears that S-HDAg prevents the rapid accumulation of editing early in the HDV genotype I replication cycle. It has been suggested that inhibition occurs by HDAg binding to HDV RNA (Polson et al. 1998); however, it is not clear whether the inhibition is due to steric effects-such as blocking of an ADAR1 binding site by HDAg-or HDAg-mediated sequestration of HDV RNA in a cellular compartment in which ADAR1 is not active. Whether the ability of HDAg to inhibit editing varies during the course of viral RNA replication remains to be determined. In contrast to the sensitivity of genotype I amber/W site editing to S-HDAg, editing at the amber/W site in the genotype III double hairpin structure is not inhibited by S-HDAg (Cheng et al. 2003). The hairpin denoted SL2, on the 3' side of the amber/W site, plays an essential role (Cheng et al. 2003), and might somehow interfere with S-HDAg binding near the amber/W site.

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