Figure 1.

Mechanism of action of the components in the first combination of novel therapies for HDV, lonafarnib and interferon lambda. Inhibition of HDLAg prenylation by the farnesyltransferase inhibitor lonafarnib results in (a) virus assembly inhibition and prevention of progeny virus production, (b) accumulation of LHDAg in the cells leading to a transdominant inhibition of HDV rolling circle replication and (c) induction of innate immunity by activating interferon sensitive gene (ISG) expression. Type III IFNλ results in comparable innate immune antiviral actions as classical Type I IFNα (both activate the same pathways-d) The receptor distribution for IFNλ, however, is limited to epithelial cells, including hepatocytes (red shading-e), resulting in milder side effects compared to IFNα whose receptors are more widely distributed (most cells in the body including immune cells) (blue shading-e) FTase—farnesyltransferase; HBsAg—HBV surface antigen; ISG—interferon stimulated gene; ISRE—interferon sensitive response element; LHDAg—large HDV Antigen; SHDAg—small HDV antigen. Created with BioRender.com.