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Results for “Hepatitis Delta Virus”

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PubMedDate not supplied

Hepatitis B virus replication in acute hepatitis B, acute hepatitis B virus-hepatitis delta virus coinfection and acute hepatitis delta superinfection.

To evaluate the effect of hepatitis delta virus on the level of replication of hepatitis B virus and to assess the clinical significance that such an effect might have on the final outcome of the infection, the serological profile of hepatitis B virus DNA was investigated in 153 patients with acute or chronic hepatitis B virus infection with or without associated delta infection. Serum hepatitis B virus DNA was detected in 57% of patients with acute hepatitis B, 67% of those with acute hepatitis B virus-hepatitis delta virus coinfection and 25% of HBsAg carriers with hepatitis delta virus superinfection during the first week after the onset of symptoms. Patients with acute hepatitis B and those with acute hepatitis B virus-hepatitis delta virus coinfection did not differ significantly with respect to the serological profile of hepatitis B virus DNA and final clinical outcome. Within the group of HBsAg carriers with hepatitis delta virus superinfection, all patients who were initially negative for hepatitis B virus DNA developed chronic hepatitis delta virus infection, whereas 3 of the 4 patients with active hepatitis B virus infection at the time of superinfection showed transient inhibition of hepatitis B virus replication followed by termination of hepatitis delta virus infection in two patients. Therefore, although delta virus may inhibit the replication of hepatitis B virus among chronic HBsAg carriers, this effect is not readily apparent among patients with hepatitis B virus-hepatitis delta virus coinfection.

Acute Disease↗

PubMed1994

Mutational analysis of delta antigen: effect on assembly and replication of hepatitis delta virus.

Hepatitis delta virus requires a helper function from hepatitis B virus for packaging, release, and infection of hepatocytes. The assembly of large delta antigen (HDAg) is mediated by copackaging with the small surface antigen of hepatitis B virus (HBsAg), and the assembly of small HDAg requires interactions with large HDAg. To examine the molecular mechanisms by which small HBsAg, large HDAg, and small HDAg interact, we have established a virion assembly system in COS7 cells by cotransfecting plasmids encoding the small HBsAg, the small HDAg, and large HDAg mutants. Results indicate that sequences within the C-terminal 19-amino-acid domain flanking the Cxxx isoprenylation motif are important for the assembly of large HDAg. In addition, a large HDAg mutant bearing extra sequences separating the C-terminal 19-amino-acid domain from the common regions of the small and large HDAgs is capable, like the wild-type large HDAg, of copackaging with small HBsAg. The ability of assembly is also demonstrated for a large HDAg mutant from which nuclear localization signals have been removed. Furthermore, a cryptic signal within the N-terminal 50 amino acid residues other than the putative N-terminal coiled-coil structure and a subdomain between amino acid residues 50 and 65 of the large HDAg are important for the assembly of small HDAg as well as the trans-dominant negative regulation of large HDAg in hepatitis delta virus replication.

Amino Acid Sequence↗

PubMed1996

N-linked glycosylation of hepatitis B surface antigens is involved but not essential in the assembly of hepatitis delta virus.

Hepatitis delta virus (HDV) is a defective virus requiring the hepatitis B virus (HBV) to provide hepatitis B surface antigens as the envelope protein. The hepatitis B surface antigens are posttranslationally modified by N-linked glycosylation, and its significance in HDV assembly was investigated with a cotransfection system using human hepatoma cell line Huh-7. After the N-linked glycosylation of HBsAg was blocked by tunicamycin treatment, the packaging of HDV in the culture system could be suppressed to a level as low as 5-10% of the untreated control. The extent of inhibition correlated with the increased concentrations of tunicamycin. In contrast, the loss of HBsAg glycosylation did not affect the efficiency of assembly of HBV particles. When the N-linked glycosylation site of small HBsAg at amino acid 146 was mutated from asparagine to glutamine, the mutant HBsAg packaged only a modest amount of HDV particles. The quantity and kinetics of formation of HDV particles in culture system were reduced by the depletion of HBsAg glycosylation. Therefore HDV, similar to influenza and vesicular stomatitis viruses, depends on glycosylation of the envelope proteins as a signal for envelope protein maturation and for virion formation.

Amino Acid Sequence↗

PubMed1995

Molecular biologic and pathogenetic analysis of hepatitis delta virus.

Hepatitis delta virus (HDV) consists of an envelope derived from hepatitis B virus (HBV) and a nucleocapsid consisting of hepatitis delta antigen and a circular RNA genome. Both the delta antigen and the RNA possess many unique properties which play crucial roles in the life cycle of HDV. They may also contribute indirectly to the mechanism of viral pathogenesis.

Antigens, Viral↗

PubMed2006

Hepatitis delta virus.

Hepatitis delta virus (HDV) is a sub-viral agent that is dependent for its life cycle on hepatitis B virus (HBV). The help it obtains from HBV is limited to the sharing of envelope proteins. These proteins are needed to facilitate the assembly of the HDV genome into new virus particles, and in turn, to allow the attachment and entry of HDV into new host cells. In other respects, the replication of the small single-stranded circular RNA genome of HDV is independent of HBV. HDV genome replication produces two forms of a RNA-binding protein known as the long and small delta antigens (Ag). All other proteins needed for HDV genome replication, especially the RNA-directed RNA polymerase activity, are provided by the host cell. This mini-review article is a mixture of personal perspective and speculations about the future of HDV research. It starts with a brief overview of HDV and its replication, notes some of the major unresolved questions, and directs the interested reader to more detailed reviews.

Animals↗

PubMed1988

Chronic HDV (hepatitis delta virus) hepatitis. Intrahepatic expression of delta antigen, histologic activity and outcome of liver disease.

The expression of intrahepatic delta antigen (HDAg) was studied in relation to the morphologic features of HDV hepatitis and the outcome of liver disease. The study was performed in 101 patients followed up for an average of 12 years; one or more liver biopsies were available from each patient, giving a total of 167 specimens. The histologic features were assessed using numerical scores. A significant positive relation was observed between the number of HDAg-positive cells and the extent of portal inflammation (Spearman's rank coefficient 0.75). The highest degree of inflammation and intrahepatic expression of HDAg was found before the elimination of the virus, while the outcome of HDV disease was unrelated to the severity of the initial morphologic lesion. These results suggest that the individual immune response may play an important role in the pathogenesis of HDV hepatitis.

Adolescent↗

PubMed1998

Inhibition of Cellular RNA polymerase II transcription by delta antigen of hepatitis delta virus.

Hepatitis delta virus (HDV) contains a circular, viroid-like RNA and the hepatitis delta antigen (HDAg) protein. The viral RNA is replicated via RNA-dependent RNA synthesis, which is thought to be mediated by host DNA-dependent RNA polymerase II (pol II). The precise mechanism of HDV RNA replication using RNA as a template remains to be elucidated, though it is clear that HDAg is involved. We demonstrate here that both SP1-activated and basal pol II transcription are inhibited by HDAg. This inhibitory effect of HDAg was observed in vivo in transient cotransfection assays as well as in vitro in HeLa nuclear extracts with purified, recombinant HDAg. The in vitro inhibition of pol II transcription could be reversed with excess HeLa nuclear extracts. Furthermore, HDAg specifically inhibited pol II-mediated transcription but not pol I- or III-mediated transcription. These results provide support for the model in which HDAg participates in a complex with host cell pol II transcription factors to mediate pol II-dependent HDV RNA replication, concomitantly cellular pol II transcription.

Chloramphenicol O-Acetyltransferase↗

PubMed1994

Requirements for editing in the genomic RNA of hepatitis delta virus.

Hepatitis delta virus is a satellite of the hepatitis B virus which provides the surface antigen for the viral coat. The genome of the hepatitis delta virus consists of a single-stranded, circular RNA of 1679 nucleotides which forms a rod structure due to a high extent of self homology and which replicates via synthesis of an antigenomic RNA in a rolling circle mechanism similar to plant viroids. The antigenomic RNA contains the open reading frame for the delta-antigen which exists in two isoforms, p24 and p27. The formation of these two isoforms is explained by RNA editing at nucleotide 1012 which changes the stop translation codon UAG at amino acid residue 196 into the codon UGG for tryptophan and extends the open reading frame for the synthesis of p27. In order to investigate whether the editing occurs cotranscriptionally during RNA replication or is a posttranscriptional base modification in the genomic or antigenomic RNA, replication defective deletion mutants of the HDV genome were constructed and expressed in COS-7 cells. Editing was demonstrated in non-replicating fragments of genomic HDV RNA but not in antigenomic HDV RNA fragments. The sequences from nucleotide position 337-1200 of the genomic RNA were sufficient to enable low levels of editing. Editing at position 1012 required the opposite strand of the RNA rod from nucleotide position 337-783. Replicating circular HDV RNA was much more efficiently edited than non-replicating full length genomic HDV RNA. Expression of delta-antigen in trans did not complement the low editing efficiency of replication defective genomic HDV RNA. These results demonstrate posttranscriptional U to C editing in the genomic HDV RNA and exclude misincorporation during HDV RNA replication as the editing mechanism. The minimal structural requirements for HDV RNA editing reside between nucleotide position 337-1200.

Animals↗

PubMed2006

RNA editing in hepatitis delta virus.

Hepatitis delta virus (HDV) relies heavily on host functions and on structural features of the viral RNA. A good example of this reliance is found in the process known as HDV RNA editing, which requires particular structural features in the HDV antigenome, and a host RNA editing enzyme, ADAR1. During replication, the adenosine at the amber/W site in the HDV antigenome is edited to inosine. As a result, the amber stop codon in the hepatitis delta antigen (HDAg) open reading frame is changed to a tryptophan codon and the reading frame is extended by 19 or 20 codons. Because these extra amino acids alter the functional properties of HDAg, this change serves a critical purpose in the HDV replication cycle. Analysis of the RNA secondary structures and regulation of editing in HDV genotypes I and III has indicated that although editing is essential for both genotypes, there are substantial differences. This review covers the mechanisms of RNA editing in the HDV replication cycle and the regulatory mechanisms by which HDV controls editing.

Adenosine↗

PubMed1995

The molecular biology of hepatitis delta virus.

Hepatitis delta virus (HDV) contains a circular, viroid-like RNA genome, the only animal viral RNA of its kind. It possesses a ribozyme activity, which can autocatalytically cleave and ligate itself. The ribozyme has a unique structural requirement different from other known ribozymes. HDV RNA undergoes RNA-dependent RNA replication via a double rolling circle mechanism, which is probably mediated by cellular RNA polymerase II, utilizing modified cellular transcription machineries. HDV RNA encodes a single protein, hepatitis delta antigen, which is a nuclear, RNA-binding phosphoprotein and required for viral RNA replication. During replication, HDV RNA undergoes a specific RNA editing event to extend its open reading frame and produce a longer, isoprenylated delta antigen, which suppresses RNA replication and initiates viral particle assembly. Ribozyme, cell-mediated RNA-dependent RNA replication, and RNA editing are some of the unique properties and unresolved issues of the molecular biology of HDV.

Animals↗

PubMed1992

The structure and replication of hepatitis delta virus.

Hepatitis delta virus exists in nature as a satellite of hepatitis B virus. This review emphasizes studies during the past few years that have clarified much about this satellite relationship. Many unique and intriguing features have been assigned to delta and its replication. In addition, certain unresolved questions are emphasized, and consideration is even given to the application of delta as a vector.

Hepatitis Delta Virus↗

PubMed2003

In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus.

Hepatitis delta virus (HDV) can dramatically worsen liver disease in patients coinfected with hepatitis B virus (HBV). No effective medical therapy exists for HDV. The HDV envelope requires HBV surface antigen proteins provided by HBV. Once inside a cell, however, HDV can replicate its genome in the absence of any HBV gene products. In vitro, HDV virion assembly is critically dependent on prenyl lipid modification, or prenylation, of its nucleocapsid-like protein large delta antigen. To overcome limitations of current animal models and to test the hypothesis that pharmacologic prenylation inhibition can prevent the production of HDV virions in vivo, we established a convenient mouse-based model of HDV infection capable of yielding viremia. Such mice were then treated with the prenylation inhibitors FTI-277 and FTI-2153. Both agents were highly effective at clearing HDV viremia. As expected, HDV inhibition exhibited duration-of-treatment dependence. These results provide the first preclinical data supporting the in vivo efficacy of prenylation inhibition as a novel antiviral therapy with potential application to HDV and a wide variety of other viruses.

Alkyl and Aryl Transferases↗

PubMedDate not supplied

Pathogenesis associated with replication of hepatitis delta virus.

Hepatitis delta virus (HDV) is a subviral satellite of human hepatitis B virus (HBV). HDV was discovered in patients chronically infected with HBV who had a more severe form of disease. Subsequent studies have attempted to understand the cytopathic effects due to HDV, and this article reviews the progress along with newer studies that suggest that HDV genome replication per se causes no more than a moderate inhibition of cellular growth rate. This inhibition nevertheless provides a selective pressure for reduced levels of HDV genome replication. Such a reduction is apparently achieved by a host cell activity that edits the HDV RNA genome.

Animals↗

PubMed2004

Identification of novel HLA-A*0201-restricted CD8+ T-cell epitopes on hepatitis delta virus.

Hepatitis delta virus (HDV) superinfection causes a poor prognosis in hepatitis B virus-infected patients and effective therapy is lacking. Cytotoxic T-lymphocyte (CTL) responses play an important role in the pathogenesis of chronic viral hepatitis; however, the CD8+ T-cell epitopes of HDV have never been defined. Potential HLA-A*0201-restricted HDV peptides were selected from the SYFPEITHI database and screened by T2 cell-stabilization assay. HLA-A*0201 transgenic mice on a C57BL/6 background were injected intramuscularly with an HDV DNA vaccine. Splenocytes were stained directly ex vivo with HLA-A*0201-peptide tetramers after immunization. Epitope-specific CTL responses were confirmed by cytotoxic assays. HLA-A2, chronically infected HDV patients were also enrolled, to assess the existence of HDV-specific CD8+ T cells, based on findings in animals. Following HDV DNA vaccination, nearly 0.9 % of the total splenic CD8+ T cells were specific for peptides HDV 26-34 and HDV 43-51 in HLA-A*0201 transgenic mice, which was significantly higher than the number found in non-transgenic mice or in transgenic mice that had been immunized with control plasmid. HDV 26-34- and 43-51-specific CTL lines were able to produce CTL responses to each peptide. Interestingly, HDV 26-34- and HDV 43-51-specific CD8+ T cells were also detectable in two chronically infected HDV patients in the absence of active HDV replication. In conclusion, HDV 26-34 and 43-51 are novel HLA-A*0201-restricted CTL epitopes on genotype I HDV. HDV 26-34- and 43-51-specific CTLs have been detected in chronic hepatitis delta patients without active disease. Evoking CTL responses to HDV may be an alternative approach to controlling HDV viraemia in patients with chronic hepatitis delta.

Amino Acid Sequence↗

PubMed1996

Replication of hepatitis delta virus.

Hepatitis delta virus (HDV) is a unique viroid-like human pathogen that is always associated with hepatitis B infection. Replication of HDV involves the transcription of genomic RNA, probably by the host RNA polymerase II, by a rolling circle mechanism followed by self-cleavage and self-ligation. Editing of antigenomic RNA, possibly involving the enzyme adenosine deaminase, generates two functionally distinct forms of delta antigen. The molecular basis for HDV pathogenicity remains uncertain.

Aminohydrolases↗

PubMed1992

[Synthesis and antigenic activity of peptides of the nucleocapsid protein of the hepatitis delta virus].

Hepatitis delta virus (HDV), a recently discovered infectious agent, participates in severe, often lethal forms of acute and chronic hepatitis and liver cirrhosis. Based on theoretical analysis of secondary structure, hydrophilicity and acrophilicity data, several regions of HDV antigen, presumably containing B-epitopes, have been revealed and the corresponding peptides have been synthesized by the solid phase method. All the peptides obtained reacted with the respective antipeptide rabbit sera. The peptides and their conjugates with BSA or KLH were used for ELISA with individual and pooled anti-HD-positive sera from patients with chronic delta hepatitis. The high antigenicity of the peptide 65-80 shows that one of the antigenically active regions of HDAg is situated between these amino acid residues and that the peptide may be used for detection of anti-HD antibodies in patients blood sera.

Amino Acid Sequence↗

PubMed2006

Eighth major clade for hepatitis delta virus.

Hepatitis delta virus is the only representative of the Deltavirus genus, which consists of 7 differentiated major clades. In this study, an eighth clade was identified from 3 distinct strains. Deltavirus genetic variability should be considered for diagnostic purposes. Clinical consequences of the diversity have yet to be evaluated.

Cote d'Ivoire↗

PubMed1994

Cis- and trans-acting ribozymes from a human pathogen, hepatitis delta virus.

Hepatitis delta virus (HDV) contains two self-cleaving RNA sequences (ribozymes) that may naturally function as such in human cells. A pseudo-knot-containing structural motif, which is distinct from the well-characterized secondary structures of self-cleaving RNAs common to the plant pathogenic RNAs, is shared by the cis-acting HDV ribozymes. Definition of the sequences and secondary structures of the HDV ribozymes has facilitated the design of novel catalytic molecules, such as small RNA circles, capable of site-specific cleavage of RNA in trans.

Animals↗