Download Glenn JS, 2006 Vietheer PT, 2005 Global Anti

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