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Attachment of HDV through HBsAg = HBsAg Pre S1 sequence in L protein nucleus hepatocyte = HDV HDV transferred to nucleus = HBsAg = HDV nucleus hepatocyte HDV transferred to nucleus = HBsAg =HDV- RNA nucleus hepatocyte Cell Ligase HDV Ribozyme? Replication of HDV-RNA + + + = genomic HDV-RNA = antigenomic HDV-RNA + HOST RNA polymerase II, I, III HDV Ribozyme - Cell Ligase HDV Ribozyme? Replication of HDV-RNA - + = genomic HDV-RNA = antigenomic HDV-RNA - HOST RNA polymerase II, I, III HDV Ribozyme + Assembly of HDV virions = HBsAg = HDV-RNA - + - + + + - nucleus hepatocyte Assembly of HDV virions = HBsAg = HDV - + - + + + - nucleus hepatocyte Virion assembly Assembly of HDV virions = HBsAg = HDV - + - + + + - nucleus hepatocyte Virion assembly Life cycle of HDV directed by post-translational modification of HDAg = HBsAg = HDV Transfer HDAg Acetylation - + - Farnesylation - Methylation + Phosphorilation + - Sumoylation + Export nucleus Replication Virion Assembly Therapeutic targets? Inactivated by Myrcludex = HBsAg = HDV Transfer Attachment - + - Blocked by farnesylation inhibitors - + + - + Export nucleus Replication Virion Assembly Liver transplantation for end-stage HDV disease • Valid treatment, survival good • Risk of graft reinfection distinctly lower than HBV • HBIG with antivirals protect virtually every transplant Latent HDV infection in liver How long does it persist? Up to 3 years in human liver grafts Rizzetto, 2006; Moderacke, 2011 Even six weeks after initiating HDV infection, HBV can be used to superinfect with assembly and release of infectious HDV Lugehetmann, Hepatology, 2011 A NEW MODEL OF HUMAN INFECTION?