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Features of the HDV RNA Transcribed by host RNA Polymerase II Self-cleavage of RNA by internal ribozyme elements Extensive Base-Pairing A RNA Editing G HDV RIBOZYME A ribozyme structurally and biochemically related to the HDV ribozyme is present in an intron of the human CPEB3 gene, which belongs to a family of gene regulating messanger RNA polyadenilation. HDV EVOLVED FROM THE HUMAN TRANSCRIPTOME? Salehi-Ashtian K, 2006 HDV EVOLVED FROM A SMALLER VIROID, ACQUIRED HD-AG AND RIBOZYME THROUGH RECOMBINATION WITH THE HUMAN Brazas R, 1996 TRANSCRIPTOME? HDV RIBOZYME The only catalytic cleaving RNA motif discovered in humans, ideal for use as a functional enzyme in an intracellular environment • HDV sequences in the human CPEB3 gene, not recognized as an external, invading RNA • functions properly in the low-ionic enviroment of human cells • more stable and longer half life than hammerhead or hairpin ribozymes HDV RIBOZYME AS A GENE INACTIVATION TOOL Replication Scheme of HDV CXXX HDV-proteins: functions • promote replication • promote virion formation • coiled-coil domains proteins interactions • bipartite nuclear localization signal • arginine-rich motifs • activation of reporter genes • promote elongation RNA Pol II proteins drive to nucleus RNA binding How can HDV proteins orchestrate the lifecycle of HDV? By post-translational modifications: HDAg/HDV-RNA = ONE-GENE GENOME phosphorilation acetylation methylation prenylation HDV: unique features in human virology • Smallest infectious agent in man • Similar to viroids and satellite RNAs of plants • Infectious at 10-11 serum dilutions in HBsAg + • Rolling circle mechanism of replication • Self-cleaving and self-ligating ribozyme • Transcription by a host-RNA polymerase II HDV virion assembly requires: On HDV side: Prenylation (farnesylation) of the terminal CXXX box of Large HD-Ag On HBV side: Integrity of critical regions of the HBsAg HDV VIRION ASSEMBLY: blocked in-vitro and in-vivo by prenylation inhibitors Glenn JS, 2006 inhibited by changes in SW 196 L/S of the small HBsAg induced by Lamivudine Vietheer PT, 2005 Global Anti-HDV Prevalence in HBsAg Carriers (15,000,000 Positive) Modified from: Radjef et al., 2004, and Pujol et al., 2005 Drug addicts Prevalence of anti-HD in HBsAg-carriers with liver disease in Italy N° patients tested 822 30 24.6% % 1.556 996 441 23% 14% 20 8% 10 0 1978-81 Smedile 1983 1987 1992 1997 Sagnelli 1992 Sagnelli 1997 Gaeta 2000 Prevalence changes of anti-HD in CHB and LC in Turkey within the years % anti-HD (n° examined) CHB LC 19801990 31% (204) 43.3% (302) 19912000 19.4% (4271) 26.1% (157) 20012005 11% (1486) 24% (805) CHB: Chronic hepatitis B, LC: Liver cirrhosis Degertekin H et al, 2006 Decline in HDV Prevalence: Control of HBV Improved socioeconomic and hygienic conditions Precautions for the control of HIV Universal HBV vaccination IN THE DEVELOPING WORLD No control of HDV as long as HBV remains unchecked Significant presence of HDV reported in the last 4 years from: PAKISTAN1 VIETNAM5 INDIA2 TAJIKISTAN6 MONGOLIA3 TUNISIA7 IRAN4 MAURETANIA8 1. Zuberi BF, 2006; 2. Acharya SK, 2006; 3.Tsatsralt-Od B, 2006; 4. Roshandel G, 2007; 5. Nguyen VT, 2007; 6. Khan A, 2008; 7. Djebbi A, 2009; 8. Lunel F, personal communication Prevalence of anti-HD in HBsAg-carriers with liver disease in Italy N° patients tested 30 % 822 24.6% 1.556 996 441 1.069 8% 11% 2001 23% 14% 20 10 0 1978-81 Smedile 1983 1987 1992 1997 Sagnelli 1992 Sagnelli 1997 Gaeta 2000 Sagnelli 2008 Wedemeyer H, 2007 Contemporary HDV, North-Europe Anti-HD/HBsAg+ HDV origin 11.3% (253/2354) 26% Turkey 28% East Europe 8.5% (87/962) 28.1% South, East Europe 26.8% Africa 7.3% Middle East Hanover1 1992-2006 London2 2000-2006 1. Wedemeyer H., 2007; 2. Cross TJS, 2008; 3. Contemporary HDV: France origin of 617 anti-HD+ patients Africa West Europe East Europe Asia 2001 2002 2003 2004 2005 2006 Le Gal F, 2007 IN EUROPE: Significant residual reservoir of HDV, composed of two HBsAg pools: • ageing domestic survivors of the 1970-1980 epidemic • young immigrants from HDV endemic areas recapitulating florid hepatitis D 2009 : • immigrants 2010s