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PubMed1991

Direct immunofluorescence testing of haired skin, nasal planum, and footpads of clinically normal woodchuck hepatitis virus-infected and non-infected woodchucks.

The purpose of this study was to determine the frequency of immunoreactant deposition in the skin, footpad, and nasal planum of 10 clinically normal, non WHV-infected woodchucks. The second part of the study investigated the frequency of immunoreactant deposition at the same sites in clinically normal, WHV-infected woodchucks, and compared these results with those reported in humans. Direct immunofluorescence testing of the haired skin, footpad, and nasal planum of all normal and 9 of the 10 WHV-infected woodchucks was negative. The footpad of 1 WHV-infected woodchuck revealed immunoreactant deposition in the walls of the superficial dermal blood vessels.

Animals↗
PubMed1990

Autoantibody pattern in a woodchuck model of hepatitis B.

Spectrum, dynamics, and immunoglobulin class of the non-organ specific autoantibodies were investigated in 646 sequential sera from 18 woodchucks with experimental woodchuck hepatitis virus (WHV) infection and in 8 naturally infected chronic carriers of the virus. Among examined WHV carriers, 8 animals developed hepatocellular carcinoma. The sera were tested by indirect immunofluorescence for autoantibodies against smooth muscle (SMA), nuclei (ANA), brush border of proximal renal tubuli (ABBA), and mitochondria (AMA). Analysis revealed that inoculation with WHV was followed by the appearance and/or meaningful elevation of the titre of SMA in IgG class. In all 18 experimentally infected woodchucks, the autoantibody rise preceded the appearance of viral serologic markers (WHsAg and/or WHeAg) by 1 to 4 weeks (mean +/- SD = 2.5 +/- 1.5 weeks). Once induced, SMA remained steadily detectable achieving the peak titre value around week 12 postinoculation. The SMA dynamics did not parallel with the fluctuation of the virus serologic markers and they were similar both in animals who recovered from acute episodes and in those who progressed to chronic infection. In chronic carriers, contrasted to acute infection, fluctuation of SMA titre even to undetectable levels and frequent parallel rises and falls of SMA, ANA, and ABBA titres were observed. A different pattern was found in all three chronic carriers who acquired infection from mothers. In this group, high and relatively stable autoantibody levels were detected. Development of hepatocellular carcinoma was not associated with any specific autoantibody pattern. This study revealed that WHV invasion undoubtedly induces non-organ specific autoimmune response.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Hepadna virus nucleocapsid and surface antigens and the antigen-specific antibodies associated with hepatocyte plasma membranes in experimental woodchuck acute hepatitis.

Hepatocyte plasma membranes purified from five woodchucks with distinct serologic and histologic patterns of experimentally induced acute woodchuck hepatitis virus (WHV) infection were studied to determine the virus antigens expression and anti-viral specificity of the bound immunoglobulins. WHV core, e, and surface antigens (WHcAg, WHeAg, and WHsAg, respectively) were analyzed with the use of immunoblotting technique both in the native form of these membranes and in the membranes treated with high molar urea or a nonionic detergent. The eluted material was tested either for the presence of WHV antigens or reactivity of the antibodies directed to the virus antigens. The data revealed that acute WHV infection is accompanied by hepatocyte plasma membrane expression of all three viral antigens tested. In all cases, native membranes displayed both WHeAg and WHsAg, whereas WHcAg presence was detected in hepatocyte plasma membranes after their disruption with urea or a detergent. The data indicated that a part or, in some instances, even the whole detectable WHcAg specificity can be incorporated into plasma membrane structure in such a way that it is not accessible for recognition by the specific antibodies (anti-WHc), suggesting at least a partial functional disability of this antigen as a target for immunologic reactions in in vivo conditions. In contrast, WHeAg specificity was detectable in all native membrane preparations studied and its expression was not evidently influenced by the employed treatments, whereas that of WHsAg tended to decline. Further, anti-WHc reactivity was identified in all membrane eluates tested, but antibodies to WHeAg (anti-WHe) were exclusively found in the material eluted from membranes originating from woodchucks with borderline histologic activity of acute hepatitis, which cleared away e antigen from the serum shortly before liver perfusion. Antibodies to WHsAg (anti-WHs) did not show up in the eluates. The present findings demonstrated that WHeAg specificity is not only exposed on the surface of infected hepatocytes, but is also relatively more easily accessible for serologic recognition than that of WHcAg in acute WHV infection. The above observation suggests that e antigen can serve as a potential plasma membrane target for hepatocytolytic attack in addition to that of WHsAg or WHcAg. Moreover, the results of this study demonstrated an apparent relationship between low histologic activity of liver inflammation, e antigen clearance from the circulation, and detectability of hepatocyte plasma membrane-bound anti-e antibodies in acute hepadna viral hepatitis.

Acute Disease↗
PubMed1989

Hepadnaviruses and hepatocellular carcinoma (HCC).

Members of the hepadnavirus family share properties of virion structure, genome structure and replication, epidemiologic behavior, and pathogenic effects. Persistent infections with hepatitis B virus (HBV) in man, woodchuck hepatitis virus (WHV) in Marmota monax, ground squirrel hepatitis virus (GSHV) in Spermophilus beecheyi, and duck hepatitis B virus (DHBV) in domestic ducks of China are associated with development of hepatocellular carcinoma (HCC). Epidemiological evidence implicating hepadnavirus infection in HCC includes the observation that the geographic distributions of HBV infection and HCC are similar, that the incidence of HCC is much higher in hepadnavirus-infected than uninfected hosts, and that viral DNA sequences are integrated in the cellular DNA of most (e.g., 80 to 90%), but not all, hepadnavirus-associated HCC. Cirrhosis further increases the risk of HCC in HBV-infected humans. The precise role of hepadnaviruses in development of most HCC is unclear, although the finding of viral integrations within or near protooncogenes in a few cases suggests the possibility that these integrations may play a direct role in these HCC. However, in the great majority of HCC, viral integrations are in different cellular DNA sites in different HCC, integrations are not within domains of known protooncogenes, and integrations are not found in some 10 to 15% hepadnavirus-associated HCC, suggesting that persisting viral sequences are not directly involved in the development of these HCC as viral sequences are for tumors caused by viruses with oncogenes or viruses that act by a "promoter-insertion" mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Liver diseases associated with hepadnavirus infection. A study in duck model.

Among four hepadnaviruses, we studied liver diseases of duck hepatitis B virus (HBV)-infected animals. There was close correlation of viral infection and development of liver diseases. The presence of hepatocellular carcinoma (HCC) was observed in Chinese ducks. We previously showed that duck HBV DNA was integrated in the neoplastic cells. Analysis of duck HBV integrants revealed the similarity to the reported structures of HBV integrants. To develop effective antiviral therapy, we tested adenine arabinoside (Ara-A), phosphonoformate, azido-deoxythymidine (AZT), and dideoxycytidine (DDC) in this in vivo model. Significant suppressive effects on viral replication were observed by phosphonoformate and adenine arabinoside, but AZT and DDC failed to show significant antiviral effects. This may be related to a unique pathway of replication in hepadnaviruses.

Animals↗
PubMed1995

Sequences and structures at hepadnaviral integration: recombination sites implicate topoisomerase I in hepadnaviral DNA rearrangements and integration.

We have previously shown that eukaryotic topoisomerase I (topo I) can mediate hepadnaviral integration in vitro. To investigate further the possible in vivo significance of topo I in hepadnaviral integration and to detect additional important factors, we have generated an extensive compilation of hepadnaviral recombination sites from chronically infected liver tissues and hepatocellular carcinomas. These sequences were subjected to various established sequence and structural analyses. Our investigation provides evidence that topo I can mediate hepadnaviral integration and rearrangement in vivo. During integration, free ends can be exposed to other nuclear enzymes, resulting in the addition of 'filler DNA'. In other cases, junctional homologies between viral and cellular DNA may facilitate integration. Structural analysis suggests that torsional stress may act on the cellular target sites, possibly promoting the integration process. A mechanism is proposed by which hepadnavirus integration into the host chromosomes is primarily mediated by topo I.

Base Sequence↗
PubMed1995

Synergistic hepatocarcinogenic effect of hepadnaviral infection and dietary aflatoxin B1 in woodchucks.

Interactive hepadnaviral and chemical hepatocarcinogenesis was studied in woodchucks inoculated as newborns with woodchuck hepatitis virus (WHV), which is closely related to the human hepatitis B virus. When the woodchucks reached 12 months of age, aflatoxin B1 (AFB1) was administered in the diet at dose levels of 40 micrograms/kg body weight/day for 4 months and subsequently 20 micrograms/kg body weight/day (5 days/week) for lifetime. WHV DNA was demonstrated by Southern blot hybridization in the serum and by PCR in the serum and/or liver tissue. The histo- and cytomorphology of the liver were investigated by light and electron microscopy. WHV carriers with and without AFB1 treatment developed a high incidence of preneoplastic foci of altered hepatocytes, hepatocellular adenomas, and hepatocellular carcinomas that appeared 6-26 months after the beginning of the combination experiment. Administration of AFB1 to WHV carriers resulted in a significantly earlier appearance of hepatocellular neoplasms and a higher incidence of hepatocellular carcinomas compared to WHV carriers not treated with AFB1. Neither hepatocellular adenomas nor carcinomas (but preneoplastic foci of altered hepatocytes) were detected in woodchucks receiving AFB1 alone, and no preneoplastic or neoplastic lesions were found in untreated controls. These results provide conclusive evidence of a synergistic hepatocarcinogenic effect of hepadnaviral infection and dietary AFB1. Except for the frequent presence of ground glass cells containing surface antigen filaments in the infected woodchucks, the phenotype of preneoplastic foci of altered hepatocytes was similar in WHV carriers with and without exposure to AFB1 and in animals treated with AFB1 alone. Clear cell foci excessively storing glycogen and/or fat, amphophilic cell foci crowded with mitochondria and peroxisomes, and mixed cell foci composed of various cell types including basophilic cells rich in ribosomes predominated. The cellular phenotype in neoplastic lesions varied from clear, amphophilic, and mixed cell populations in highly differentiated adenomas and carcinomas to basophilic cell populations prevailing in poorly differentiated carcinomas. The striking similarities in altered cellular phenotypes of preneoplastic hepatic foci emerging after both hepadnaviral infection and exposure to AFB1 suggest closely related underlying molecular mechanisms that may be mainly responsible for the synergistic hepatocarcinogenic effect of these oncogenic agents.

Aflatoxin B1↗
PubMed1995

[Experimental study on anti-duck hepatitis B viral effect of Phyllanthus urinaria of different areas and combined therapy with other drugs].

The duck hepatitis B virus model was treated with phyllanthus urinaria of different area and combined with Sophora flavesceus as well as ciprofloxacin once a day for one month, the results indicated: Guangxi and Yunnan Phyllanthus could lower the serum DHBV DNA significantly (P < 0.05), but Chongqing Phyllanthus couldn't. And the amount of serum DHBV DNA rose a week after stopping of Yunnan Phyllanthus. The antiviral effect of Guangxi Phyllanthus combined with ciprofloxacin seems to be strengthened (P < 0.05).

Animals↗
PubMedDate not supplied

Characterisation of the Indian strain of duck hepatitis B virus (DHBV) and development of a carrier duck colony for antiviral drug testing.

Duck hepatitis B virus (DHBV) infected carrier ducks serve as a useful model for testing anti-hepadnavirus drugs. This needs a well characterised duck hepatitis B virus strain. We cloned and sequenced the complete genome of duck hepatitis B virus strain of Indian origin. It was 3021 nucleotides in length and had all the recognisable open reading frames (Polymerase: 20-2530 nucletides, Surface: 693-1787 nucleotides and Core: 2518-412). Using an inoculum of 50 microliters serum containing 1 x 10(11) virus particles/ml, we could infect 80% of one day old ducklings and develop a duck colony.

Animals↗
PubMed1994

State of the p53 gene in hepatocellular carcinomas of ground squirrels and woodchucks with past and ongoing infection with hepadnaviruses.

Infection with hepadnaviruses and exposure to dietary aflatoxin are considered major risk factors in the development of hepatocellular carcinoma (HCC) both in humans and in animals. Recently, a broad range of mutations in the p53 tumor suppressor gene has been reported in human HCCs, predominantly from hepatitis B virus carriers in areas with either high or low levels of exposure to dietary aflatoxin. To determine whether p53 mutations are common to HCCs of hosts infected with related hepadnaviruses with and without treatment with aflatoxin, we studied the occurrence of mutations in the p53 gene in HCCs of ground squirrels and woodchucks with history of infection with ground squirrel hepatitis virus (GSHV) and woodchuck hepatitis virus, respectively. Sequencing of wild type p53 genes from ground squirrels and woodchucks revealed remarkable homology between the two species with only a few amino acid differences in exons 4, 8, and 9. Using direct polymerase chain reaction sequencing, we analyzed the state of the p53 gene (exons 4-9) in 20 HCCs from ground squirrels (2 uninfected, 7 with past, and 11 with ongoing infection with GSHV) and in 11 HCCs from woodchucks persistently infected with woodchuck hepatitis virus. Five GSHV carrier and two uninfected ground squirrels received i.p. administration of aflatoxin B1. We detected only one mutation in the p53 gene of the tested animals. This mutation was located in codon 176 of exon 5 in the HCC of a GSHV-positive ground squirrel treated with aflatoxin. Mutation was caused by a G to T transversion in the second position of the codon, resulting in the replacement of cysteine with phenylalanine, and was accompanied by a tumor-specific loss of heterozygosity. p53 allelic amino acid variation with sequences coding for aspartic acid or asparagine was present in codon 61 in the variable region of exon 4 in both HCCs and nonneoplastic tissues of ground squirrels. In view of the considerably lower apparent rate of mutations in comparison to human HCCs, we suggest a less important role for aflatoxin in the induction of p53 mutations in HCCs of ground squirrels. Alternatively, etiological factors other than p53 mutations may be of greater significance in the development of HCC in ground squirrels and woodchucks.

Aflatoxin B1↗
PubMed1993

Hepatitis B viral clearance studies using duck virus model.

We have shown data to suggest that the in vivo duck hepatitis B virus system represents an excellent animal model system for the study of hepatitis B virus. Because of the similarity of DHBV to human HBV (including comparable results in virus inactivation studies), the high level of sensitivity of the DHBV assay, and the rapidity, ease, and relative low cost of obtaining results, we propose that the in vivo DHBV titration system be used as a model for human HBV in process validation studies. Data generated in such validation studies have, in fact, been submitted by a number of blood products manufacturers to the U.S. F.D.A. in support of IND applications.

Animals↗
PubMed1994

M13 bacteriophage DNA inhibits duck hepatitis B virus during acute infection.

We investigated effects of various DNAs on duck hepatitis B virus replication in vivo. One-day-old ducks were infected intravenously with DHBV. Various DNAs were then injected intravenously, and duck hepatitis B virus levels were followed for up to 20 days after the inoculation. When M13 bacteriophage DNA (M13 DNA), heat-denatured Escherichia coli DNA or phi X 174 phage DNA was injected intravenously at a dose of 2.45 mg/kg body wt daily for 10 days, a significant decrease of serum duck hepatitis B virus DNA was detected within 10 days. The efficacy was twice that reported with antisense DNA on a weight basis and far more than that reported on a molar basis. M13 DNA was superior, on the basis of effective dose, to acyclovir as an anti-duck hepatitis B virus agent. On treatment with M13 DNA, serum 2-5 A synthetase level was increased five to six times, suggesting that the antiviral effect of M13 DNA is at least partly due to induction of endogenous interferon, which in turn induces 2-5 A synthetase. No significant inhibitory effect on replication of duck hepatitis B virus was demonstrated by DNAs obtained from herring testes, herring sperm, salmon testes, human placenta or calf thymus. On discontinuation of M13 DNA injection on day 10, duck hepatitis B virus reappeared in the serum at later time points. Digestion of M13 DNA with S1 nuclease resulted in marked reduction of antiviral activity. These results show that M13 DNA, not its digested product, has potent antiviral activity.

2',5'-Oligoadenylate Synthetase↗