Interferon-α stimulation of liver cells enhances hepatitis delta virus RNA editing in early infection

RNA editing controls the formation of hepatitis-delta-antigen-S and -L and therefore plays a central role in the hepatitis-delta-virus (HDV) life-cycle. Editing is catalyzed by the enzyme Adenosine-deaminase-acting-on-RNA1 (ADAR1) of which two different forms, ADAR1-L and ADAR1-S, exist. As ADAR1-L is induced by interferon (IFN)-α, we examined the influence of IFN-α-stimulation of host cells on HDV-RNA editing. Editing was studied in Huh-7-cells transfected with HDV-RNA on days 7, 14, 21 and 28 after transfection. ADAR1-L mRNA was measured by RT-PCR. IFN-α-treatment led to a 5-fold higher expression of ADAR1-L and to an increase in editing from 14±2% (SD) in unstimulated controls to 27±4% (SD) on day 7 after transfection. Editing further increases over time to the same maximum level of 35% in IFN-α-treated as well as untreated cells. By IFN-α-stimulation both ADAR1-L expression and editing are increased in Huh-7-cells at day 7, and the maximum level of edited antigenomes is reached earlier with IFN-α-treatment as compared to untreated cells. Thus, ADAR1-L appears to be able to increase editing, but the HDV genome apparently has an intrinsic negative feed-back regulation mechanism that limits editing to roughly a third of the genomes.