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Features of the HDV RNA

This article explores the discovery and functions of HDV ribozyme elements in the human CPEB3 gene, which is involved in regulating mRNA polyadenylation. It discusses the evolution of HDV from the human transcriptome and its potential use as a gene inactivation tool. The unique features of HDV in human virology, including its small size, self-cleaving and self-ligating ribozyme, and transcription by host RNA polymerase II, are also discussed. The article concludes with a review of the prevalence of HDV in HBsAg carriers and the potential for control and decline of HDV through HBV precautions and vaccination.

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Features of the HDV RNA

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  1. Features of the HDV RNA Self-cleavage of RNA by internal ribozyme elements Transcribedby host RNA Polymerase II Extensive Base-Pairing A RNA Editing G

  2. 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? HDV EVOLVED FROM A SMALLER VIROID, ACQUIRED HD-AG AND RIBOZYME THROUGH RECOMBINATION WITH THE HUMAN TRANSCRIPTOME? Salehi-Ashtian K, 2006 Brazas R, 1996

  3. 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

  4. Replication Scheme of HDV CXXX

  5. HDV-proteins: functions • promote replication • promote virion formation proteins interactions • coiled-coil domains proteins drive to nucleus • bipartite nuclear localization signal • arginine-rich motifs RNA binding • activation of reporter genes • promote elongation RNA Pol II

  6. How can HDV proteins orchestrate the life-cycle of HDV? By post-translational modifications: HDAg/HDV-RNA = ONE-GENE GENOME phosphorilation acetylation methylation prenylation

  7. 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

  8. 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

  9. 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

  10. Global Anti-HDV Prevalence in HBsAg Carriers (15,000,000 Positive)

  11. Modified from: Radjef et al., 2004, and Pujol et al., 2005

  12. Drug addicts

  13. Prevalence of anti-HD in HBsAg-carriers with liver disease in Italy N° patients tested 822 1.556 996 441 30 24.6% 23% 14% 20 % 8% 10 0 1978-81 1987 1992 1997 Smedile 1983 Sagnelli 1992 Sagnelli 1997 Gaeta 2000

  14. Prevalence changes of anti-HD in CHB and LC in Turkey within the years CHB: Chronic hepatitis B, LC: Liver cirrhosis Degertekin H et al, 2006

  15. Decline in HDV Prevalence: Control of HBV Precautions for the control of HIV Improved socio-economic and hygienic conditions Universal HBV vaccination

  16. 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 INDIA2 MONGOLIA3 IRAN4 VIETNAM5 TAJIKISTAN6 TUNISIA7 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

  17. Prevalence of anti-HD in HBsAg-carriers with liver disease in Italy N° patients tested 822 1.556 996 441 1.069 30 24.6% 23% 14% 20 % 11% 8% 10 0 1978-81 1987 1992 2001 1997 Smedile 1983 Sagnelli 1992 Sagnelli 1997 Gaeta 2000 Sagnelli 2008

  18. Wedemeyer H, 2007

  19. Contemporary HDV, North-Europe 1. Wedemeyer H., 2007; 2. Cross TJS, 2008; 3.

  20. 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

  21. 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

  22. 2009 2010s : • immigrants

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