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PubMed1992

Altered glycosylation of alpha-fetoprotein in hepadnavirus-induced hepatocellular carcinoma of the woodchuck.

Altered glycosylation of alpha-fetoprotein (AFP) has been proposed as a marker of hepatocellular carcinoma (HCC) in humans. The lectin-binding properties of woodchuck AFP were investigated to determine if woodchuck hepatitis virus (WHV)-induced HCCs are also accompanied by changes in AFP glycosylation. Ninety-eight to 100% of the AFP from normal, WHV-free woodchucks with physiologic AFP elevations and from WHV-carrier woodchucks with HCC bound to concanavalin A, indicating that virtually all of the AFP was glycosylated. Three percent or less of the serum AFP of normal woodchucks bound to Lens culinaris agglutinin (LCA). In contrast, the AFP from woodchucks with HCC had an increased LCA-binding fraction (range, 8-77%). The increased LCA-binding AFP in WHV-induced HCC is analogous to that which frequently accompanies hepatitis B virus (HBV)-induced HCC in humans. This study corroborates the relationship of altered glycoconjugate synthesis to virus-induced malignant transformation, confirms the importance of AFP glycoforms as markers of HCC, and demonstrates that the WHV-infected woodchuck should be useful in investigating changes in AFP glycosylation during hepadnavirus hepatocarcinogenesis and HCC growth.

Animals↗
PubMed1995

Retroelements, reverse transcriptase and evolution.

Retroelements are genetic elements that can exist as DNA or RNA or DNA/RNA duplexes. Although retroviruses are the best known retroelements, there are many other types, including close relatives of retroviruses like LTR retrotransposons, more distant relatives like non-LTR retrotransposons, caulimoviruses and hepadnaviruses and elements with virtually no similarity, like retrons. Virtually all retroelements are 'selfish DNAs' with no involvement with the normal development or maintenance of their host cells, the only known exception being telomereres/telomerases which maintain the ends of chromosomes. Virtually all retroelements use tRNA, or RNA with strong secondary structure, to initiate their reverse transcription. The coincidence between the use of tRNA, a molecule central to the conversion of RNA to protein, with reverse transcriptase, an enzyme which is crucial for the conversion of RNA to DNA is striking, because RNA probably preceded DNA and protein in evolution. It seems plausible that retroelements were present at the genesis of living systems.

Base Sequence↗
PubMed1991

Integration of woodchuck hepatitis virus (WHV) DNA at two chromosomal sites (Vk and gag-like) in a hepatocellular carcinoma.

Integration of woodchuck hepatitis virus (WHV) DNA into the liver DNA of a woodchuck infected by the virus was investigated. Clonal viral integration was not detected three months before the appearance of four hepatocellular carcinomas (HCC). Integration of the viral DNA was detected in all four HCCs, of which one was chosen to determine the structure of the viral integration completely in a single tumor. The integration occurred in two sites. One part contains the viral DNA from the middle of the gene encoding surface antigen to two-thirds of the way through the gene encoding X protein (X) with no structural changes. The coding frame of the truncated X gene continues into the chromosomal sequence to make a possible fusion protein. The integration seems to have occurred by recombination within two direct repeats of the viral genome in one junction and by homologous recombination between viral DNA and chromosomal DNA in the other junction. The viral DNA is integrated into a spacer of the immunoglobulin L-chain Vk (IgVk) region without any chromosomal rearrangement accompanying the integration. The viral DNA at the second site has a complex structural rearrangement: part of the preS gene is duplicated and attached to the terminus of the gene encoding core antigen in a head-to-tail fashion, followed by three small fragments derived from other parts of the viral DNA. The integrated preS gene has its own 5' regulatory element and a coding frame consisting of the truncated preS gene, the other parts of viral DNA and the chromosomal sequence.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1992

Detection of mammalian and avian hepadnaviruses by the polymerase chain reaction.

The hepadnavirus family contains a number of related viruses able to infect a variety of animal species. In the present study, we have used the polymerase chain reaction and oligonucleotide primers to a conserved region of the viral replicase gene of hepadnaviruses to identify viral sequences in de novo tissues in three well-characterized hepadnavirus systems: the woodchuck, ground squirrel and Pekin duck. We did not detect related hepadnavirus sequences in liver specimens from tree squirrels putatively infected with the tree squirrel hepatitis virus, or in liver specimens from horses with hepatitis (serum sickness), or from dogs with chronic active hepatitis or hepatocellular carcinoma.

Animals↗
PubMed2005

Re-analysis of a human hepatitis B virus (HBV) isolate from an East African wild born Pan troglodytes schweinfurthii: evidence for interspecies recombination between HBV infecting chimpanzee and human.

According to current estimates, hepatitis B virus (HBV) has infected 2 billion people worldwide and among them, 360 million suffer from chronic HBV infection. Except humans, HBV or HBV-like viruses have also been isolated from different species of apes and mammals. Although recombination has been described to occur extensively between different genotypes within the human HBV lineage, no recombination event has ever been reported between human and non-human primate HBV sequences. It was our objective to perform an exhaustive search for recombination between human and non-human primate HBV strains among all available full-length human and non-human primate HBV sequences, using bootscanning and phylogenetic analyses. Intriguingly, we found that an HBV sequence isolated from a wild born Pan troglodytes schweinfurthii in East Africa-FG-is a recombinant consisting of HBV infecting chimpanzee (ChHBV) and human genotype C. More specifically, in a fragment of approximately 500 nt (positions 551-1050 spanning half of the RT domain of pol, which overlaps with half of the coding region of the small surface protein), FG grouped with HBV genotype C, while in the rest of the genome it grouped with ChHBV sequences. Phylogenetic analyses showed that in the latter region FG was more closely related to the Pan troglodytes troglodytes subspecies, forming an outlier to this group. Moreover, we show evidence that the recombination event occurred after the initial dispersion of HBV genotype C in humans. Finally, our findings point out that although rare recombination between HBV viruses infecting different species occurs.

Africa, Eastern↗
PubMed2005

Single B or T-cell epitope-based DNA vaccine using modified vector induces specific immune response against hepadnavirus.

Epitope-based DNA vaccine is an effective and powerful approach against a variety of pathogens or tumors. In present study, we reconstructed a vector that could effectively express short B and T-cell epitope of duck/hepatitis B virus, and investigated the role of the epitope-based DNA vaccination. The pUC19 was modified by inserting the compact transient framework (CTF), including HCMV IE1 promoter, enhancer, Kozak sequence, dual stop codon and 3' terminal bovine growth hormone terminal signal and so on. This modified vector was designated pEC(K) and supposed to effectively express short peptide. A well-defined single B-cell and T-cell epitope encoding gene of duck/hepatitis B virus has been synthesized as candidate epitope and cloned into pEC(K) plasmid, respectively. Transfection of the recombinant DNA into C(2)C(12) cell showed that modified plasmid could effectively express both the single B-cell and T-cell short epitope in the culture supernatant as confirmed by dot immunoblot assay (DIA). The recombinant single B and T-cell epitope-based DNA vaccine was administrated to C57BL/6 mice and could greatly induce specific humoral and CTL response. In addition, the specific antibody against B epitope could specifically bind to the DHBV particles. This report demonstrated that single epitope-based DNA vaccine using modified plasmid vector pEC(K) could induce effective specific immune responses and could be of great use for DNA vaccines.

Animals↗
PubMed2005

Effects of liver growth factors on hepadnavirus replication in chronically infected duck hepatocytes.

BACKGROUND/AIMS: Duck hepatitis B virus (DHBV) replication is up-regulated by cell cycle during the early infection of primary duck but the effect of cell cycle on DHBV replication in chronically infected hepatocyte is not known. METHODS: Hepatocytes obtained from DHBV congenitally infected embryos were used. Cell proliferation was controlled by addition of liver growth factors and the impact on viral replication analyzed. RESULTS: EGF induced cell proliferation is associated with a slight increase in CCC DNA synthesis and a decrease in viral transcription. Conversely, TGFbeta blocked cell cycle progression, diminished CCC DNA synthesis but increased viral transcription. CONCLUSIONS: Cell proliferation decreases DHBV transcription but this effect seems to be compensated by an opposite effect on the synthesis of CCC DNA resulting in a global moderate effect on viral replication. Our results also indicate that after division of chronically infected hepatocytes both daughter cells are infected, confirming that liver regeneration is not sufficient to induce CCC DNA eradication as suggested by the lack of effect of some long term anti-HBV therapies.

Animals↗
PubMed2005

Alternative methods for validation of cell culture infection with duck hepatitis B virus.

Hepatitis B virus (HBV) is an important virus used in disinfection procedures for blood spillage. However, validation of HBV inactivation is difficult, since there are no feasible infectivity assays. In some countries, the duck HBV (DHBV) is recognized as a suitable model for testing antiviral activity of chemical biocides against HBV. Currently, DHBV-infected ducks are required for preparation of the test virus as well as eggs from DHBV-free flocks for testing DHBV infectivity. To improve the practicality of the system, we suggested to use commercially available embryonated duck eggs for preparation of DHBV-susceptible hepatocyte cultures and to exclude infected hepatocytes by pre-screening with qualitative detection of DHBV DNA using polymerase chain reaction (PCR). A standardized DHBV test virus was prepared from the DHBV DNA-transfected hepatoma cell line D2, which contained 10(11)DHBV DNA molecules per mL detected by light cycler real-time PCR. Infection of cell cultures was most efficient 4 days after plating. The best identification of infected cultures was possible 6 days after infection with immunofluorescence using an antiserum against DHBV surface antigen.

Animals↗
PubMed2006

Delipidation of a hepadnavirus: Viral inactivation and vaccine development.

Many viruses including HIV, hepatitis C and hepatitis B, have an outer lipid envelope which maintains inserted viral peptides in the "correct" functional conformation and orientation. Disruption of the lipid envelope by most solvents destroys infectivity and often results in a loss of antigenicity. This communication outlines a novel approach to viral inactivation by specific solvent delipidation which modifies the whole virion rendering it non-infective, but antigenic. Duck hepatitis B virus (DHBV) was delipidated using a diisopropylether (DIPE) and butanol mixture and residual infectivity tested by inoculation into day-old ducks. Delipidation completely inactivated the DHBV (p < 0.001). Delipidated DHBV was then used to vaccinate ducks. Three doses of delipidated DHBV induced anti-DHBs antibody production and prevented high dose challenge infection in five out of six ducks. In comparison, five of six ducks vaccinated with undelipidated DHBV and four of four ducks vaccinated with glutaraldehyde inactivated DHBV were unprotected (p < 0.05). Although this solvent system completely inactivated DHBV, viral antigens were retained in an appropriate form to induce immunity. Delipidation of enveloped viruses with specific organic solvents has potential as the basis for development of vaccines.

Animals↗
PubMed2005

Genetic vaccination for production of DNA-designed antibodies specific to Hepadnavirus envelope proteins.

We propose a method of avian antibodies production based on DNA immunization of laying ducks with a plasmid encoding specified antigen, followed by egg collection and purification of egg yolk immunoglobulins (IgY). We have validated this approach in the Duck hepatitis B virus (DHBV) model. We report here that following immunization of female ducks with plasmids encoding DHBV envelope proteins, large amounts (at least 50 mg/egg) of specific antibodies can be obtained from eggs of these ducks. Interestingly, the comparison of different plasmid constructs showed the important differences in their efficacy of specific IgY antibodies induction in the sera and eggs of immunized ducks.

Animals↗
PubMed2003

A duck hepatitis B virus strain with a knockout mutation in the putative X ORF shows similar infectivity and in vivo growth characteristics to wild-type virus.

Hepadnaviruses including human hepatitis B virus (HBV) and duck hepatitis B virus (DHBV) express X proteins, HBx and DHBx, respectively. Both HBx and DHBx are transcriptional activators and modulate cellular signaling in in vitro assays. To test whether the DHBx protein plays a role in virus infection, we compared the in vivo infectivity and growth characteristics of a DHBV3 strain with a stop codon in the X-like ORF (DHBV3-X-K.O.) to those of the wild-type DHBV3 strain. Here we report that the two strains showed no significant difference in (i). their ability to induce infection that resulted in stable viraemia measured by serum surface antigen (DHBsAg) and DHBV DNA, and detection of viral proteins and replicative DNA intermediates in the liver; (ii). the rate of spread of infection in liver and extrahepatic sites after low-dose virus inoculation; and (iii). the ability to produce transient or persistent infection under balanced age/dose conditions designed to detect small differences between the strains. Thus, none of the infection parameters assayed were detectably affected by the X-ORF knockout mutation, raising the question whether DHBx expression plays a physiological role during in vivo infection with wild-type DHBV.

Animals↗
PubMed2006

Vaccination of ducks with a whole-cell vaccine expressing duck hepatitis B virus core antigen elicits antiviral immune responses that enable rapid resolution of de novo infection.

As a first step in developing immuno-therapeutic vaccines for patients with chronic hepatitis B virus infection, we examined the ability of a whole-cell vaccine, expressing the duck hepatitis B virus (DHBV) core antigen (DHBcAg), to target infected cells leading to the resolution of de novo DHBV infections. Three separate experiments were performed. In each experiment, ducks were vaccinated at 7 and 14 days of age with primary duck embryonic fibroblasts (PDEF) that had been transfected 48 h earlier with plasmid DNA expressing DHBcAg with and without the addition of anti-DHBcAg (anti-DHBc) antibodies. Control ducks were injected with either 0.7% NaCl or non-transfected PDEF. The ducks were then challenged at 18 days of age by intravenous inoculation with DHBV (5 x 10(8) viral genome equivalents). Liver biopsies obtained on day 4 post-challenge demonstrated that vaccination did not prevent infection of the liver as similar numbers of infected hepatocytes were detected in all vaccinated and control ducks. However, analysis of liver tissue obtained 9 or more days post-challenge revealed that 9 out of 11 of the PDEF-DHBcAg vaccinated ducks and 8 out of 11 ducks vaccinated with PDEF-DHBcAg plus anti-DHBc antibodies had rapidly resolved the DHBV infection with clearance of infected cells. In contrast, 10 out of 11 of the control unvaccinated ducks developed chronic DHBV infection. In conclusion, vaccination of ducks with a whole-cell PDEF vaccine expressing DHBcAg elicited immune responses that induced a rapid resolution of DHBV infection. The results establish that chronic infection can be prevented via the vaccine-mediated induction of a core-antigen-specific immune response.

Animals↗
PubMed1998

Shared motifs of the capsid proteins of hepadnaviruses and retroviruses suggest a common evolutionary origin.

The structure of the dimeric C-terminal domain of the HIV-1 capsid protein (CA), recently determined by X-ray crystallography (Gamble et al. (1997)), has a notable resemblance to the structure of the hepatitis B virus (HBV) capsid protein (Cp) dimer, previously determined by cryo-electron microscopy (Conway et al. (1997), Böttcher et al. (1997)). In both proteins, dimerization is effected by formation of a four-helix bundle, whereby each subunit contributes a helix-loop-helix and most of the interaction between subunits is mediated by one pair of helices. These are the first two observations of a motif that is common to the capsid proteins of two enveloped viruses and quite distinct from the eight-stranded anti-parallel beta-barrel found in most other virus capsid proteins solved to date (Harrison et al. (1996)). Motivated by the structural resemblance, we have examined retroviral and HBV capsid protein sequences and found weak but significant similarities between them. These similarities further support an evolutionary relationship between these two virus families of great medical importance -- the hepadnaviruses (e.g. HBV) and retroviruses (e.g. HIV).

Amino Acid Sequence↗
PubMed2003

The duck hepatitis B virus polymerase and core proteins accumulate in different patterns from their common mRNA.

Hepadnaviral reverse transcription occurs in capsids in which the core (C) protein surrounds the reverse transcriptase (P) and pregenomic RNA (pgRNA). We analyzed the accumulation patterns of duck hepatitis B virus P, C, and pgRNA in transfected LMH cells, infected primary duck hepatocytes (PDH), and infected duck liver. In all three systems, P accumulated over time in a different pattern compared with C, despite translation of both proteins from the pgRNA. Although the accumulation patterns of the proteins varied between the systems, in each case P became detectable at the same time or earlier than C and the ratio of P relative to C dropped with time. These accumulation patterns were consistent with the translation rates and half-lives of P and C. Comparing the translation rates of P and C with the pgRNA level over time revealed that translation of P and C was negatively regulated in LMH cells. These data provide a framework for comparing replication studies performed in LMH cells, PDHs and ducks.

Animals↗