Loader.rt("abs_end");
Abstract
In this study, a
method based on Principle Component Analysis and Least Square Support
Vector Machine Classifier for Expert Hepatitis Diagnosis System
(PCA–LSSVM) is introduced. This intelligent diagnosis system deals with
combination of the feature extraction and classification. This
intelligent hepatitis diagnosis system is separated into two phases: (1)
the feature extraction from hepatitis diseases database and feature
reduction by PCA, (2) the classification by LSSVM classifier. The
hepatitis diseases features were obtained from UCI Repository of Machine
Learning Databases. The number of these feature attributes are 19.
Then, number of these features was reduced to 10 from 19 by using PCA.
In second phase, these reduced features are given to inputs LSSVM
classifier. The correct diagnosis performance of the PCA–LSSVM
intelligent diagnosis system for hepatitis disease is estimated by using
classification accuracy, sensitivity and specifity analysis
respectively.
Keywords: UCI Hepatitis database; Principle
Component Analysis; Intelligent system; Least Square Support Vector
Machine Classifier
Weak T-cell reactivity to the
hepatitis B virus (HBV) is believed to be the dominant cause of chronic
HBV infection. Several lines of experimental evidence suggest that
treatment with telbivudine increases the rate of HBV e antigen (HBeAg)
loss, undetectable HBV DNA, and normalization of serum alanine
aminotransferase (ALT) in chronic hepatitis B patients (CHB). However,
it is still unclear how early antiviral therapy affects cellular immune
responses during sustained telbivudine treatment. In order to
investigate this issue, we measured detailed prospective clinical,
virological, and biochemical parameters, and we examined the frequency
of T cell subgroups as well as the ability of peripheral blood
mononuclear cells (PBMC) to respond to stimuli at five protocol time
points for 51 CHB patients who received telbivudine therapy for one
year. The preliminary data from this study revealed that
effective-treated patients showed an increased frequency of peripheral
blood CD4+T lymphocytes, an augmented proliferative response
of HBV-specific T-cells to the hepatitis B core antigen (HBcAg), and the
induction of cytokines, such as interferon gamma (IFN-γ), tumour
necrosis factor alpha (TNF-α) release at the site of infection compared
to non-responsive patients. Enhanced HBV-specific T-cell reactivity to
telbivudine therapy, which peaked at treatment week 12, was confined to a
subgroup of effective-treated patients who achieved greater viral
suppression.
Hepatitis D, also referred to as hepatitis D virus (HDV)
and classified as Hepatitis delta virus, is a disease
caused by a small circular enveloped RNA
virus. It is one of five known hepatitis
viruses: A, B,
C,
D, and E. HDV is considered to be a subviral satellite because it can
propagate only in the presence of the hepatitis
B virus (HBV).[1]
Transmission of HDV can occur either via simultaneous infection with
HBV (coinfection) or superimposed on chronic
hepatitis B or hepatitis B carrier state (superinfection).
Both superinfection and coinfection with HDV results in more severe
complications compared to infection with HBV alone. These complications
include a greater likelihood of experiencing liver failure in acute
infections and a rapid progression to liver cirrhosis,
with an increased chance of developing liver
cancer in chronic infections.[2]
In combination with hepatitis B virus, hepatitis D has the highest
mortality rate of all the hepatitis infections of 20%.
[edit] Virology
[edit] History
Hepatitis D virus was first reported in the mid-1970s, as a nuclear
antigen in patients infected with HBV who had severe liver disease [3]
This nuclear antigen was then thought to be a hepatitis B antigen and
was called the delta antigen. Following experiments in chimpanzees
showed that the hepatitis delta antigen (HDAg) was a structural part of a
pathogen that required HBV infection to replicate[4]
The entire virus was cloned and sequenced in 1986, and obtained its own
genus deltavirus [5][6]
[edit] Structure and Genome
The HDV is a small, spherical virus with a 36 nm diameter. It has an
outer coat containing three HBV envelope proteins (called large, medium,
and small hepatitis B surface antigens, and host lipids surrounding an
inner nucleocapsid. The nucleocapsid contains single-stranded, circular
RNA of 1679 nucleotides and about 200 molecules of hepatitis D antigen
(HDAg) for each genome. The hepatitis D circular genome is unique to
animal viruses because of its high GC nucleotide content. The HDV genome
exists as an enveloped negative sense, single-stranded, closed circular
RNA
nucleotide sequence is 70% self-complementary,
allowing the genome to form a partially double stranded RNA structure
that is described as rod-like.[7]
With a genome of approximately 1700 nucleotides, HDV is the smallest
"virus" known to infect animals. It has been proposed that HDV may have
originated from a class of plant viruses called viroids.[8][9]
[edit] Life Cycle
The receptor that HDV recognizes on human hepatocytes has not been
identified; however it is thought to be the same as the HBV receptor
because both viruses have the same outer coat.[10]
HDV recognizes its receptor via the N-terminal domain of the large
hepatitis B surface antigen, HBsAg.[11]
Mapping by mutagenesis of this domain has shown that aminoacid residues
9-15 make up the receptor binding site.[12]
After entering the hepatocyte, the virus is uncoated and the
nucleocapsid translocated to the nucleus due to a signal in HDAg[13]
Since the nucleocapsid does not contain an RNA polymerase to replicate
the virus’ genome, the virus makes use of the cellular RNA
polymerases Initially just RNA pol II,[14][15]
now RNA polymerases I and III have also been shown to be involved in
HDV replication[16]
Normally RNA polymerase II utilizes DNA as a template and produces
mRNA. Consequently, if HDV indeed utilizes RNA polymerase II during
replication, it would be the only known pathogen capable of using a
DNA-dependent polymerase as an RNA-dependent polymerase.
The RNA polymerases treat the RNA genome as double stranded DNA due
to the folded rod-like structure it is in. Three forms of RNA are made;
circular genomic RNA, circular complementary antigenomic RNA, and a
linear polyadenylated antigenomic RNA, which is the mRNA containing the
open reading frame for the HDAg. Synthesis of antigenomic RNA occurs in
the nucleous, mediated by RNA Pol I, whereas synthesis of genomic RNA
takes place in the nucleoplasm, mediated by RNA Pol II.[17]
HDV RNA is synthesized first as linear RNA that contains many copies of
the genome. The genomic and antigenomic RNA contain a sequence of 85
nucleotides that acts as a ribozyme, which self-cleaves the linear RNA
into monomers. This monomers are then ligated to form circular RNA [18][19]
There are eight reported genotypes of HDV with unexplained variations
in their geographical distribution and pathogenicity.
[edit] Delta antigens
A significant difference between viroids and HDV is that, while
viroids produce no proteins, HDAg is the only protein known to be coded
for by the HDV genome. It consist of two forms; a 27kDa large-HDAg, and a
small-HDAg of 24kDa. The N-terminals of the two forms are identical,
they differ by 19 more amino acids in the C-terminal of the large HDAg.[20]
Both isoforms are produced from the same reading frame which contains
an UAG stop codon at codon 196, which normally produces only the
small-HDAg. However, editing by cellular enzyme adenosine deaminase-1
changes the stop codon to UCG, allowing the large-HDAg to be produced [20][21]
Despite having 90% identical sequences, these two proteins play
diverging roles during the course of an infection. HDAg-S is produced in
the early stages of an infection and enters the nucleus and supports
viral replication. HDAg-L, in contrast, is produced during the later
stages of an infection, acts as an inhibitor of viral replication, and
is required for assembly of viral particles.[22][23][24]
Thus RNA editing by the cellular enzymes is critical to the virus’ life
cycle because it regulates the balance between viral replication and
virion assembly.
[edit] Transmission
The routes of transmission of hepatitis D are similar to those for
hepatitis B. Infection is largely restricted to persons at high risk of
hepatitis B infection, particularly injecting drug users and persons
receiving clotting factor concentrates. Worldwide more than 15 million
people are co-infected. HDV is rare in most developed countries, and is mostly associated with intravenous drug use. However, HDV is much more common in
the immediate Mediterranean region, sub-Saharan Africa, the Middle
East, and the northern part of South America.[25]
In all, about 20 million people may be infected with HDV.[26]
[edit] See also
[edit] References
Loader.rt("abs_end");
Abstract
The evolutionary and
mutational pattern of full hepatitis B virus (HBV) quasispecies during
sequential nucleos(t)ide analog (NUC) therapy remains unclear. In this
study, full-length HBV clones were generated from serial serum samples
of five chronic hepatitis B patients who received sequential NUC
therapies (treated patients) and two untreated patients with acute
flares. The evolutionary and mutational patterns of full HBV
quasispecies were studied. In the three treated patients who received
lamivudine as initial antiviral therapy, nucleotide polymorphism and
nonsynonymous divergence all decreased at lamivudine breakthrough but
increased after rescue therapies. Conversely, two other treated patients
showed a distinct change in divergence during adefovir–telbivudine
sequential therapies. Untreated subjects exhibited increased
polymorphism and divergence in the preC/C region at ALT flare.
Four of the treated patients presented amino acid changes in the “a”
determinant during NUC therapy. All of the treated subjects showed amino
acid changes within the known T-cell or B-cell epitopes in the surface
or core antigen, most of which were accompanied by mutations in reverse
transcriptase (RT) region. Co-variations in the core promoter, the preC
region and in the known epitopes of the preS gene accompanied by RT
mutations, were common. In untreated patients, most of these
co-variations located in the preC/C gene. In conclusion, the
distribution of genetic variability of HBV shows remarkably different patterns
between the treated and untreated subjects and the quasispecies
divergence of different regions of HBV may vary remarkably even within a
single host.Abstract
Die Klinik der
Virushepatitiden B, C und D ist ähnlich, bei der akuten Infektion reicht
sie von völlig asymptomatischem bis zu schwerem ikterischen Verlauf mit
in seltenen Fällen auftretendem Leberversagen. Dabei verläuft die akute
Hepatitis D schwerer und die akute Hepatitis C leichter. Die chronische
Virushepatitis ist durch geringe oder nur wenige Symptome
gekennzeichnet, vor allem Müdigkeit und Oberbauchschmerzen stehen im
Vordergrund. In einem Teil der Patienten entwickeln sich über die Zeit
Symptome des fortgeschrittenen Leberschadens und der Zirrhose.
Die Diagnose der Hepatitis B wird durch den Nachweis
des HBsAg gestellt, die der Hepatitis D durch das Anti-HDV. Die
Hepatitis C wird durch die Virus-RNA diagnostiziert, als Screeningtest
eignet sich das Anti-HCV. Zum Verlauf wird bei der Hepatitis B die
HBV-DNA bestimmt; bei der Hepatitis C wird die Quantifizierung der
Virus-RNA zum Therapie-Monitoring genutzt. Die Leberbiopsie hat ihren
Stellenwert in der Bestimmung des Stadiums und der Aktivität der
Lebererkrankung.
Hepatitis D virus (HDV)
infection involves a distinct subgroup of individuals simultaneously
infected with the hepatitis B virus (HBV) and characterized by an often
severe chronic liver disease. HDV is a defective RNA agent needing the
presence of HBV for its life cycle. HDV is present worldwide, but the
distribution pattern is not uniform. Different strains are classified
into eight genotypes represented in specific regions and associated with
peculiar disease outcome. Two major specific patterns of infection can
occur, i.e. co-infection with HDV and HBV or HDV superinfection of a
chronic HBV carrier. Co-infection often leads to eradication of both
agents, whereas superinfection mostly evolves to HDV chronicity.
HDV-associated chronic liver disease (chronic hepatitis D) is
characterized by necro-inflammation and relentless deposition of
fibrosis, which may, over decades, result in the development of
cirrhosis. HDV has a single-stranded, circular RNA genome. The virion is
composed of an envelope, provided by the helper HBV and surrounding the
RNA genome and the HDV antigen (HDAg). Replication occurs in the
hepatocyte nucleus using cellular polymerases and via a rolling circle
process, during which the RNA genome is copied into a full-length,
complementary RNA. HDV infection can be diagnosed by the presence of
antibodies directed against HDAg (anti-HD) and HDV RNA in serum.
Treatment involves the administration of pegylated interferon-α and is
effective in only about 20% of patients. Liver transplantation is
indicated in case of liver failure.y. Despite recent advances in
the treatment of chronic viral hepatitis, therapy of chronic hepatitis D
is not yet satisfactory. The only option currently available is
interferon-α (IFN), whose efficacy is related to the dose and duration
of treatment. However, the rate of sustained hepatitis D virus (HDV)
clearance after a 1-year course with high doses of standard IFN is low.
Better results have recently been reported with pegylated IFN both in
IFN-naïve and in previous nonresponders to standard IFN, suggesting the
use of pegylated IFN as a first-line therapy in chronic hepatitis D.
Nucleoside analogues that inhibit hepatitis B virus (HBV) are
ineffective against HDV and combination therapy with lamivudine or
ribavirin has not shown significant advantages over monotherapy with
either standard or pegylated IFN. Because the ultimate goal of treatment
is eradication of both HDV and HBV, in responders IFN therapy should be
continued as long as possible until the loss of hepatitis B surface
antigen, adjusting the dose to patient tolerance. However, because
side-effects are common, continuous monitoring is mandatory. Although
the first results obtained with pegylated IFN have been encouraging, the
rate of sustained virological response is still low and the rate of
relapse high, emphasizing the need for developing novel classes of
antivirals specifically interfering with the life cycle of this unique
virus.
To investigate the presence
of serum hepatitis delta virus antigen by immunoblot and its correlation
with other markers of active viral replication (intrahepatic hepatitis D
antigen, IgM antibody to hepatitis D and serum hepatitis D virus RNA),
we studied serum samples from 50 patients with chronic hepatitis D virus
infection (38 with and 12 without intrahepatic hepatitis D antigen). Of
the 38 patients with intrahepatic hepatitis D antigen, 27 (71%) had
antigen detectable in seurm by immunoblot, whereas only two were
reactive by conventional enzyme-linked immunosorbent assay. Thirty-one
(82%) patients were also positive for serum hepatitis D virus RNA by
spot hybridization and 33 (87%) were positive for IgM anti-hepatitis D
virus. All markers were simultaneously present in 24 patients.
Circulating hepatitis D antigen was detected in one (8%), IgM
antihepatitis D in seven (58%) and hepatitis D virus RNA in two (17%) of
the 12 patients who had anti-hepatitis D in serum but not detectable
hepatitis D antigen in liver. Hepatitis D antigen was not detected in
serum of any of the 15 control patients.
The
results suggest that serum hepatitis D antigen as detected by
immunoblot and serum hepatitis D virus RNA are similar in sensitivity
for detection of active hepatitis D virus replication during chronic
infection and constitute useful, sensitive and noninvasive tests for the
diagnosis and monitoring of chronic hepatitis D virus infection.
Abstract
In this study, a
method based on Principle Component Analysis and Least Square Support
Vector Machine Classifier for Expert Hepatitis Diagnosis System
(PCA–LSSVM) is introduced. This intelligent diagnosis system deals with
combination of the feature extraction and classification. This
intelligent hepatitis diagnosis system is separated into two phases: (1)
the feature extraction from hepatitis diseases database and feature
reduction by PCA, (2) the classification by LSSVM classifier. The
hepatitis diseases features were obtained from UCI Repository of Machine
Learning Databases. The number of these feature attributes are 19.
Then, number of these features was reduced to 10 from 19 by using PCA.
In second phase, these reduced features are given to inputs LSSVM
classifier. The correct diagnosis performance of the PCA–LSSVM
intelligent diagnosis system for hepatitis disease is estimated by using
classification accuracy, sensitivity and specifity analysis
respectively.
Keywords: UCI Hepatitis database; Principle
Component Analysis; Intelligent system; Least Square Support Vector
Machine Classifier
Weak T-cell reactivity to the
hepatitis B virus (HBV) is believed to be the dominant cause of chronic
HBV infection. Several lines of experimental evidence suggest that
treatment with telbivudine increases the rate of HBV e antigen (HBeAg)
loss, undetectable HBV DNA, and normalization of serum alanine
aminotransferase (ALT) in chronic hepatitis B patients (CHB). However,
it is still unclear how early antiviral therapy affects cellular immune
responses during sustained telbivudine treatment. In order to
investigate this issue, we measured detailed prospective clinical,
virological, and biochemical parameters, and we examined the frequency
of T cell subgroups as well as the ability of peripheral blood
mononuclear cells (PBMC) to respond to stimuli at five protocol time
points for 51 CHB patients who received telbivudine therapy for one
year. The preliminary data from this study revealed that
effective-treated patients showed an increased frequency of peripheral
blood CD4+T lymphocytes, an augmented proliferative response
of HBV-specific T-cells to the hepatitis B core antigen (HBcAg), and the
induction of cytokines, such as interferon gamma (IFN-γ), tumour
necrosis factor alpha (TNF-α) release at the site of infection compared
to non-responsive patients. Enhanced HBV-specific T-cell reactivity to
telbivudine therapy, which peaked at treatment week 12, was confined to a
subgroup of effective-treated patients who achieved greater viral
suppression.
| Classification and external resources | |
and classified as Hepatitis delta virus, is a disease
caused by a small circular enveloped RNA
virus. It is one of five known hepatitis
viruses: A, B,
C,
D, and E. HDV is considered to be a subviral satellite because it can
propagate only in the presence of the hepatitis
B virus (HBV).[1]
Transmission of HDV can occur either via simultaneous infection with
HBV (coinfection) or superimposed on chronic
hepatitis B or hepatitis B carrier state (superinfection).
Both superinfection and coinfection with HDV results in more severe
complications compared to infection with HBV alone. These complications
include a greater likelihood of experiencing liver failure in acute
infections and a rapid progression to liver cirrhosis,
with an increased chance of developing liver
cancer in chronic infections.[2]
In combination with hepatitis B virus, hepatitis D has the highest
mortality rate of all the hepatitis infections of 20%.
Contents [hide]
|
[edit] History
Hepatitis D virus was first reported in the mid-1970s, as a nuclear
antigen in patients infected with HBV who had severe liver disease [3]
This nuclear antigen was then thought to be a hepatitis B antigen and
was called the delta antigen. Following experiments in chimpanzees
showed that the hepatitis delta antigen (HDAg) was a structural part of a
pathogen that required HBV infection to replicate[4]
The entire virus was cloned and sequenced in 1986, and obtained its own
genus deltavirus [5][6]
[edit] Structure and Genome
The HDV is a small, spherical virus with a 36 nm diameter. It has an
outer coat containing three HBV envelope proteins (called large, medium,
and small hepatitis B surface antigens, and host lipids surrounding an
inner nucleocapsid. The nucleocapsid contains single-stranded, circular
RNA of 1679 nucleotides and about 200 molecules of hepatitis D antigen
(HDAg) for each genome. The hepatitis D circular genome is unique to
animal viruses because of its high GC nucleotide content. The HDV genome
exists as an enveloped negative sense, single-stranded, closed circular
RNA
nucleotide sequence is 70% self-complementary,
allowing the genome to form a partially double stranded RNA structure
that is described as rod-like.[7]
With a genome of approximately 1700 nucleotides, HDV is the smallest
"virus" known to infect animals. It has been proposed that HDV may have
originated from a class of plant viruses called viroids.[8][9]
[edit] Life Cycle
The receptor that HDV recognizes on human hepatocytes has not been
identified; however it is thought to be the same as the HBV receptor
because both viruses have the same outer coat.[10]
HDV recognizes its receptor via the N-terminal domain of the large
hepatitis B surface antigen, HBsAg.[11]
Mapping by mutagenesis of this domain has shown that aminoacid residues
9-15 make up the receptor binding site.[12]
After entering the hepatocyte, the virus is uncoated and the
nucleocapsid translocated to the nucleus due to a signal in HDAg[13]
Since the nucleocapsid does not contain an RNA polymerase to replicate
the virus’ genome, the virus makes use of the cellular RNA
polymerases Initially just RNA pol II,[14][15]
now RNA polymerases I and III have also been shown to be involved in
HDV replication[16]
Normally RNA polymerase II utilizes DNA as a template and produces
mRNA. Consequently, if HDV indeed utilizes RNA polymerase II during
replication, it would be the only known pathogen capable of using a
DNA-dependent polymerase as an RNA-dependent polymerase.
The RNA polymerases treat the RNA genome as double stranded DNA due
to the folded rod-like structure it is in. Three forms of RNA are made;
circular genomic RNA, circular complementary antigenomic RNA, and a
linear polyadenylated antigenomic RNA, which is the mRNA containing the
open reading frame for the HDAg. Synthesis of antigenomic RNA occurs in
the nucleous, mediated by RNA Pol I, whereas synthesis of genomic RNA
takes place in the nucleoplasm, mediated by RNA Pol II.[17]
HDV RNA is synthesized first as linear RNA that contains many copies of
the genome. The genomic and antigenomic RNA contain a sequence of 85
nucleotides that acts as a ribozyme, which self-cleaves the linear RNA
into monomers. This monomers are then ligated to form circular RNA [18][19]
There are eight reported genotypes of HDV with unexplained variations
in their geographical distribution and pathogenicity.
[edit] Delta antigens
A significant difference between viroids and HDV is that, while
viroids produce no proteins, HDAg is the only protein known to be coded
for by the HDV genome. It consist of two forms; a 27kDa large-HDAg, and a
small-HDAg of 24kDa. The N-terminals of the two forms are identical,
they differ by 19 more amino acids in the C-terminal of the large HDAg.[20]
Both isoforms are produced from the same reading frame which contains
an UAG stop codon at codon 196, which normally produces only the
small-HDAg. However, editing by cellular enzyme adenosine deaminase-1
changes the stop codon to UCG, allowing the large-HDAg to be produced [20][21]
Despite having 90% identical sequences, these two proteins play
diverging roles during the course of an infection. HDAg-S is produced in
the early stages of an infection and enters the nucleus and supports
viral replication. HDAg-L, in contrast, is produced during the later
stages of an infection, acts as an inhibitor of viral replication, and
is required for assembly of viral particles.[22][23][24]
Thus RNA editing by the cellular enzymes is critical to the virus’ life
cycle because it regulates the balance between viral replication and
virion assembly.
[edit] Transmission
The routes of transmission of hepatitis D are similar to those for
hepatitis B. Infection is largely restricted to persons at high risk of
hepatitis B infection, particularly injecting drug users and persons
receiving clotting factor concentrates. Worldwide more than 15 million
people are co-infected. HDV is rare in most developed countries, and is mostly associated with intravenous drug use. However, HDV is much more common in
the immediate Mediterranean region, sub-Saharan Africa, the Middle
East, and the northern part of South America.[25]
In all, about 20 million people may be infected with HDV.[26]
[edit] See also
- Hepatitis A
- Hepatitis B and Hepatitis B in China
- Hepatitis C
- Hepatitis E
- Hepatitis F
- Hepatitis G
[edit] References
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virus RNA". Nature 329 (6137): 343–6. doi:10.1038/329343a0. PMID 3627276. - ^ Fattovich G, Giustina G, Christensen E et al.
(March 2000). "Influence of hepatitis delta virus
infection on morbidity and mortality in compensated cirrhosis type B.
The European Concerted Action on Viral Hepatitis (Eurohep)". Gut
46 (3): 420–6. doi:10.1136/gut.46.3.420. PMC 1727859. PMID 10673308. [ندعوك للتسجيل في المنتدى أو التعريف بنفسك لمعاينة هذا الرابط] - ^ Rizzetto, M; Canese MG, Arico S, Criello O,
Trepo C, Bonino F, Verme G (1997). "Immunofluorescence detection of new
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(12): 997–1003. PMC 1411847. PMID 75123. - ^ Rizzetto, M; Canese, MG, Purcell, RH, London,
WT, Sly, LD, Gerin, JL (1981 Nov-Dec). "Experimental HBV and delta
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Najarian, RC, Thayer, RM, Mullenbach, GT, Denniston, KJ, Gerin, JL,
Houghton, M (1986 Oct 9-15). "Structure, sequence and expression of the
hepatitis delta (delta) viral genome". Nature 323 (6088):
508–14. doi:10.1038/323508a0. PMID 3762705. - ^ Fauquet, CM; Mayo MA, Maniloff J, Desselberger
U, Ball LA (2005). "Deltavirus". Eight Report of the International
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1990). "Cloning and sequencing of RNA of
hepatitis delta virus isolated from human serum". J. Gen. Virol.
71 ( Pt 7) (7): 1603–6. doi:10.1099/0022-1317-71-7-1603. PMID 2374010. [ندعوك للتسجيل في المنتدى أو التعريف بنفسك لمعاينة هذا الرابط] - ^ Elena SF, Dopazo J, Flores R, Diener TO, Moya A
(July 1991). "Phylogeny of viroids, viroidlike
satellite RNAs, and the viroidlike domain of hepatitis delta virus RNA".
Proc. Natl. Acad. Sci. U.S.A. 88 (13): 5631–4. doi:10.1073/pnas.88.13.5631. PMC 51931. PMID 1712103. [ندعوك للتسجيل في المنتدى أو التعريف بنفسك لمعاينة هذا الرابط] - ^ Sureau, C (2006). "The role of the HBV
envelope proteins in the HDV replication cycle". Current topics in
microbiology and immunology. Current Topics in Microbiology and
Immunology 307: 113–31. doi:10.1007/3-540-29802-9_6. ISBN 978-3-540-29801-4. PMID 16903223. - ^ Barrera, A; Guerra, B, Notvall, L, Lanford, RE
(2005 Aug). "Mapping of the hepatitis B virus pre-S1 domain involved in
receptor recognition". Journal of virology 79 (15):
9786–98. doi:10.1128/JVI.79.15.9786-9798.2005.
PMC 1181564. PMID 16014940. - ^ Engelke, M; Mills, K, Seitz, S, Simon, P,
Gripon, P, Schnölzer, M, Urban, S (2006 Apr). "Characterization of a
hepatitis B and hepatitis delta virus receptor binding site". Hepatology
(Baltimore, Md.) 43 (4): 750–60. doi:10.1002/hep.21112. PMID 16557545. - ^ Schulze, A; Schieck, A, Ni, Y, Mier, W, Urban,
S (2010 Feb). "Fine mapping of pre-S sequence requirements for
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"Characterization of nuclear targeting signal of hepatitis delta
antigen: nuclear transport as a protein complex". Journal of virology
66 (2): 914–21. PMC 240792. PMID 1731113. - ^ Lehmann E, Brueckner F, Cramer P (November
2007). "Molecular basis of RNA-dependent RNA polymerase II activity". Nature
450 (7168): 445–9. doi:10.1038/nature06290. PMID 18004386. - ^ Filipovska J, Konarska MM (January 2000). "Specific HDV RNA-templated
transcription by pol II in vitro". RNA 6 (1): 41–54. doi:10.1017/S1355838200991167. PMC 1369892. PMID 10668797. [ندعوك للتسجيل في المنتدى أو التعريف بنفسك لمعاينة هذا الرابط] - ^ Greco-Stewart, VS; Schissel, E, Pelchat, M
(2009-03-30). "The hepatitis delta virus RNA genome interacts with the
human RNA polymerases I and III". Virology 386 (1): 12–5. doi:10.1016/j.virol.2009.02.007. PMID 19246067. - ^ Li, YJ; Macnaughton, T, Gao, L, Lai, MM (2006
Jul). "RNA-templated replication of hepatitis delta virus: genomic and
antigenomic RNAs associate with different nuclear bodies". Journal of
virology 80 (13): 6478–86. doi:10.1128/JVI.02650-05. PMC 1488965. PMID 16775335. - ^ Branch, AD; Benenfeld, BJ, Baroudy, BM, Wells,
FV, Gerin, JL, Robertson, HD (1989-02-03). "An ultraviolet-sensitive
RNA structural element in a viroid-like domain of the hepatitis delta
virus". Science 243 (4891): 649–52. doi:10.1126/science.2492676. PMID 2492676. - ^ Wu, HN; Lin, YJ, Lin, FP, Makino, S, Chang,
MF, Lai, MM (1989 Mar). "Human hepatitis delta virus RNA subfragments
contain an autocleavage activity". Proceedings of the National
Academy of Sciences of the United States of America 86 (6):
1831–5. doi:10.1073/pnas.86.6.1831. PMC 286798. PMID 2648383. - ^ a
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Abstract
The evolutionary and
mutational pattern of full hepatitis B virus (HBV) quasispecies during
sequential nucleos(t)ide analog (NUC) therapy remains unclear. In this
study, full-length HBV clones were generated from serial serum samples
of five chronic hepatitis B patients who received sequential NUC
therapies (treated patients) and two untreated patients with acute
flares. The evolutionary and mutational patterns of full HBV
quasispecies were studied. In the three treated patients who received
lamivudine as initial antiviral therapy, nucleotide polymorphism and
nonsynonymous divergence all decreased at lamivudine breakthrough but
increased after rescue therapies. Conversely, two other treated patients
showed a distinct change in divergence during adefovir–telbivudine
sequential therapies. Untreated subjects exhibited increased
polymorphism and divergence in the preC/C region at ALT flare.
Four of the treated patients presented amino acid changes in the “a”
determinant during NUC therapy. All of the treated subjects showed amino
acid changes within the known T-cell or B-cell epitopes in the surface
or core antigen, most of which were accompanied by mutations in reverse
transcriptase (RT) region. Co-variations in the core promoter, the preC
region and in the known epitopes of the preS gene accompanied by RT
mutations, were common. In untreated patients, most of these
co-variations located in the preC/C gene. In conclusion, the
distribution of genetic variability of HBV shows remarkably different patterns
between the treated and untreated subjects and the quasispecies
divergence of different regions of HBV may vary remarkably even within a
single host.Abstract
Die Klinik der
Virushepatitiden B, C und D ist ähnlich, bei der akuten Infektion reicht
sie von völlig asymptomatischem bis zu schwerem ikterischen Verlauf mit
in seltenen Fällen auftretendem Leberversagen. Dabei verläuft die akute
Hepatitis D schwerer und die akute Hepatitis C leichter. Die chronische
Virushepatitis ist durch geringe oder nur wenige Symptome
gekennzeichnet, vor allem Müdigkeit und Oberbauchschmerzen stehen im
Vordergrund. In einem Teil der Patienten entwickeln sich über die Zeit
Symptome des fortgeschrittenen Leberschadens und der Zirrhose.
Die Diagnose der Hepatitis B wird durch den Nachweis
des HBsAg gestellt, die der Hepatitis D durch das Anti-HDV. Die
Hepatitis C wird durch die Virus-RNA diagnostiziert, als Screeningtest
eignet sich das Anti-HCV. Zum Verlauf wird bei der Hepatitis B die
HBV-DNA bestimmt; bei der Hepatitis C wird die Quantifizierung der
Virus-RNA zum Therapie-Monitoring genutzt. Die Leberbiopsie hat ihren
Stellenwert in der Bestimmung des Stadiums und der Aktivität der
Lebererkrankung.
Hepatitis D virus (HDV)
infection involves a distinct subgroup of individuals simultaneously
infected with the hepatitis B virus (HBV) and characterized by an often
severe chronic liver disease. HDV is a defective RNA agent needing the
presence of HBV for its life cycle. HDV is present worldwide, but the
distribution pattern is not uniform. Different strains are classified
into eight genotypes represented in specific regions and associated with
peculiar disease outcome. Two major specific patterns of infection can
occur, i.e. co-infection with HDV and HBV or HDV superinfection of a
chronic HBV carrier. Co-infection often leads to eradication of both
agents, whereas superinfection mostly evolves to HDV chronicity.
HDV-associated chronic liver disease (chronic hepatitis D) is
characterized by necro-inflammation and relentless deposition of
fibrosis, which may, over decades, result in the development of
cirrhosis. HDV has a single-stranded, circular RNA genome. The virion is
composed of an envelope, provided by the helper HBV and surrounding the
RNA genome and the HDV antigen (HDAg). Replication occurs in the
hepatocyte nucleus using cellular polymerases and via a rolling circle
process, during which the RNA genome is copied into a full-length,
complementary RNA. HDV infection can be diagnosed by the presence of
antibodies directed against HDAg (anti-HD) and HDV RNA in serum.
Treatment involves the administration of pegylated interferon-α and is
effective in only about 20% of patients. Liver transplantation is
indicated in case of liver failure.y. Despite recent advances in
the treatment of chronic viral hepatitis, therapy of chronic hepatitis D
is not yet satisfactory. The only option currently available is
interferon-α (IFN), whose efficacy is related to the dose and duration
of treatment. However, the rate of sustained hepatitis D virus (HDV)
clearance after a 1-year course with high doses of standard IFN is low.
Better results have recently been reported with pegylated IFN both in
IFN-naïve and in previous nonresponders to standard IFN, suggesting the
use of pegylated IFN as a first-line therapy in chronic hepatitis D.
Nucleoside analogues that inhibit hepatitis B virus (HBV) are
ineffective against HDV and combination therapy with lamivudine or
ribavirin has not shown significant advantages over monotherapy with
either standard or pegylated IFN. Because the ultimate goal of treatment
is eradication of both HDV and HBV, in responders IFN therapy should be
continued as long as possible until the loss of hepatitis B surface
antigen, adjusting the dose to patient tolerance. However, because
side-effects are common, continuous monitoring is mandatory. Although
the first results obtained with pegylated IFN have been encouraging, the
rate of sustained virological response is still low and the rate of
relapse high, emphasizing the need for developing novel classes of
antivirals specifically interfering with the life cycle of this unique
virus.
To investigate the presence
of serum hepatitis delta virus antigen by immunoblot and its correlation
with other markers of active viral replication (intrahepatic hepatitis D
antigen, IgM antibody to hepatitis D and serum hepatitis D virus RNA),
we studied serum samples from 50 patients with chronic hepatitis D virus
infection (38 with and 12 without intrahepatic hepatitis D antigen). Of
the 38 patients with intrahepatic hepatitis D antigen, 27 (71%) had
antigen detectable in seurm by immunoblot, whereas only two were
reactive by conventional enzyme-linked immunosorbent assay. Thirty-one
(82%) patients were also positive for serum hepatitis D virus RNA by
spot hybridization and 33 (87%) were positive for IgM anti-hepatitis D
virus. All markers were simultaneously present in 24 patients.
Circulating hepatitis D antigen was detected in one (8%), IgM
antihepatitis D in seven (58%) and hepatitis D virus RNA in two (17%) of
the 12 patients who had anti-hepatitis D in serum but not detectable
hepatitis D antigen in liver. Hepatitis D antigen was not detected in
serum of any of the 15 control patients.
The
results suggest that serum hepatitis D antigen as detected by
immunoblot and serum hepatitis D virus RNA are similar in sensitivity
for detection of active hepatitis D virus replication during chronic
infection and constitute useful, sensitive and noninvasive tests for the
diagnosis and monitoring of chronic hepatitis D virus infection.
