Features of the HDV RNA

1
Features of the HDV RNA
Self-cleavage of RNA by internal ribozyme elements
Transcribed by 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
anti-HD (n examined) anti-HD (n examined) anti-HD (n examined) anti-HD (n examined)
1980-1990 1991-2000 2001-2005
CHB 31 (204) 19.4 (4271) 11 (1486)
LC 43.3 (302) 26.1 (157) 24 (805)
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
Anti-HD/HBsAg HDV origin
Hanover1 1992-2006 11.3 (253/2354) 26 Turkey 28 East Europe
London2 2000-2006 8.5 (87/962) 28.1 South, East Europe 26.8 Africa 7.3 Middle East
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
Le Gal F, 2007
2001
2002
2003
2004
2005
2006
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
2010s
2009

• immigrants