Inhibition of duck hepatitis B virus replication by purine 2′,3′-dideoxynucleosides

Suzuki, Satoru; Lee, Bonita; Luo, Weixing; Tovell, Dorothy R.; Robins, Morris J.; Tyrrell, D. Lorne

doi:10.1016/s0006-291x(88)80752-6

Cited by 48 publications

(24 citation statements)

References 18 publications

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“…Primary duck hepatocytes (PDHs) from 14-to 21-day-old ducklings were prepared by using collagenase as previously described (34). The resulting PDHs were plated at 750,000 cells per well in six-well plates and cultured at 37°C in Leibovitz 15 medium supplemented with 1.2 g of insulin/ml, 1.7 g of glucose/ml, 11 M hydrocortisone hemisuccinate, 15 mM HEPES, 5% fetal bovine serum, 50 IU of penicillin/ml, 10 g of streptomycin/ml, and 25 g of nystatin/ml (PDH medium).…”

Section: Methodsmentioning

confidence: 99%

Superinfection Exclusion in Duck Hepatitis B Virus Infection Is Mediated by the Large Surface Antigen

Walters

Joyce

Addison

et al. 2004

J Virol

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Superinfection exclusion is the phenomenon whereby a virus prevents the subsequent infection of an already infected host cell. The Pekin duck hepatitis B virus (DHBV) model was used to investigate superinfection exclusion in hepadnavirus infections. Superinfection exclusion was shown to occur both in vivo and in vitro with a genetically marked DHBV, DHBV-ClaI, which was unable to establish an infection in either DHBVinfected ducklings or DHBV-infected primary duck hepatocytes (PDHs). In addition, exclusion occurred in vivo even when the second virus had a replicative advantage. Superinfection exclusion appears to be restricted to DHBV, as adenovirus, herpes simplex virus type 1, and vesicular stomatitis virus were all capable of efficiently infecting DHBV-infected PDHs. Exclusion was dependent on gene expression by the original infecting virus, since UV-irradiated DHBV was unable to mediate the exclusion of DHBV-ClaI. Using recombinant adenoviruses expressing DHBV proteins, we determined that the large surface antigen mediated exclusion. The large surface antigen is known to cause down-regulation of a DHBV receptor, carboxypeptidase D (CPD). Receptor down-regulation is a mechanism of superinfection exclusion seen in other viral infections, and so it was investigated as a possible mechanism of DHBV-mediated exclusion. However, a mutant large surface antigen which did not down-regulate CPD was still capable of inhibiting DHBV infection of PDHs. In addition, exclusion of DHBV-ClaI did not correlate with a decrease in CPD levels. Finally, virus binding assays and confocal microscopy analysis of infected PDHs indicated that the block in infection occurs after internalization of the second virus. We suggest that superinfection exclusion may result from the role of the L surface antigen as a regulator of intracellular trafficking.Hepadnaviruses are a family of enveloped, hepatotropic viruses with small (3.0-to 3.2-kb), partially double-stranded DNA genomes (28). The family includes viruses infecting the woodchuck, ground squirrel, grey heron, snow goose, and Pekin duck (duck hepatitis B virus [DHBV]) as well as the medically important human hepatitis B virus (HBV).The virion is an icosahedral capsid made up of a core protein surrounded by a lipid bilayer that contains the viral envelope proteins. Contained within the capsid is the viral genome with the polymerase protein covalently attached to the 5Ј terminus of the minus strand. The hepadnavirus genome is organized into overlapping reading frames that encode the precore, core, polymerase, and surface proteins. The mammalian hepadnaviruses, as well as the majority of the avian hepadnaviruses, contain an additional open reading frame that encodes the X protein (10). Infection is initiated by the interaction of the virus with a receptor present on the surface of hepatocytes. Carboxypeptidase D (CPD) has been identified as a receptor for DHBV, although it appears that additional coreceptors are required (4,7,35). Following attachment, the virus enters the cell, likely by ...

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Section: Methodsmentioning

confidence: 99%

Superinfection Exclusion in Duck Hepatitis B Virus Infection Is Mediated by the Large Surface Antigen

Walters

Joyce

Addison

et al. 2004

J Virol

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“…On day 7, medium was VOL. 47,2003 LAMIVUDINE-RESISTANT HEPATITIS B VIRUS 1937 on May 9, 2018 by guest http://aac.asm.org/ harvested from the cells and HBV ECV DNA present in the culture supernatant was quantitated as previously described (22). Medium samples were also analyzed for the production of HBsAg and HBeAg.…”

Section: Methodsmentioning

confidence: 99%

“…Primary hepatocytes from ducks congenitally infected with duck HBV have also been used to screen drugs for activity against hepadnaviruses (9,47). However, neither of these systems can be used to study the effects of antivirals on the lamivudine-resistant HBV.…”

mentioning

confidence: 99%

Generation of Stable Cell Lines Expressing Lamivudine-Resistant Hepatitis B Virus for Antiviral-Compound Screening

Walters

Allen

Condreay

et al. 2003

Antimicrob Agents Chemother

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Lamivudine [␤-L-(؊)-2,3-dideoxy-3-thiacytidine] is a potent inhibitor of hepadnavirus replication and is used both to treat chronic hepatitis B virus (HBV) infections and to prevent reinfection of transplanted livers.Unfortunately, lamivudine-resistant HBV variants do arise during prolonged therapy, indicating a need for additional antiviral drugs. Replication-competent HBV constructs containing the reverse transcriptase domain L180M/M204V and M204I (rtL180M/M204V and rtM204I) mutations associated with lamivudine resistance were used to produce stable cell lines that express the resistant virus. These cell lines contain stable integrations of HBV sequences and produce both intracellular and extracellular virus. HBV produced by these cell lines was shown to have a marked decrease in sensitivity to lamivudine, with 450-and 3,000-fold shifts in the 50% inhibitory concentrations for the rtM204I and rtL180M/M204V viruses, respectively, compared to that for the wild-type virus. Drug assays indicated that the lamivudine-resistant virus exhibited reduced sensitivity to penciclovir [9-(4-hydroxy-3-hydroxymethyl-but-1-yl) guanine] but was still inhibited by the nucleoside analogues CDG (carbocyclic 2-deoxyguanosine) and abacavir { [1S,4R]-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol}. Screening for antiviral compounds active against the lamivudineresistant HBV can now be done with relative ease.Over 350 million people worldwide are chronically infected with hepatitis B virus (HBV) despite the availability of an effective vaccine. Chronic HBV infection is associated with both cirrhosis and hepatocellular carcinoma (4,5,33). Until recently, the only licensed treatment available was alpha interferon, which has a response rate of only 30 to 40% in selected patients (51). The (Ϫ) enantiomer of 2Ј-dideoxy-3Ј-thiacytidine, also known as lamivudine, is a potent inhibitor of HBV replication (11,12,16,41). Lamivudine is phosphorylated by cellular deoxycytidine kinases. This triphosphate form of lamivudine then competes with cellular dCTP and is incorporated by the viral polymerase, causing premature chain termination during both the reverse transcription and DNA synthesis steps of HBV DNA synthesis (45).Chronically infected individuals treated with long-term lamivudine therapy show histological improvement and a significant reduction of viral load (15,27,28). Lamivudine has also been shown to be beneficial in both the prevention and treatment of reinfection of livers transplanted into HBV carriers (3,7,8,19,37). A drawback to lamivudine therapy is that the template for hepadnavirus replication, covalently closed circular DNA (cccDNA), is relatively unaffected by lamivudine (36). Although the half-life of HBV cccDNA in humans has not been established, the half-lives of both duck HBV and woodchuck HBV cccDNA have been shown to be quite long. Both are estimated to be between 30 and 57 days (1, 56). Because of the apparent stability of cccDNA, continuous suppression of HBV replication will likely require lon...

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“…a purine dideoxynucleoside analogue, has been reported to inhibit HBV replication in 2.2.15 cells (Korba and Gerin, 1992;Koszalka et sl., 1995) and in vivo using a Pekin duck model (Suzuki et a/., 1988;Lee et et., 1989). The recent demonstration of the stereoselectivity of HBV DNA polymerase (Schinazi et el., 1994;Furman et et., 1995) has provided the stimulation to synthesize the corresponding enantiomer as well as other~-L purine analogues.…”

Section: Anti-hbv Activity Off3-l-dda and Derivatives 277mentioning

confidence: 99%

Inhibition of Hepatitis B Virus Replication by Nucleoside Enantiomers of β-2′,3′-Dideoxypurine Analogues

Alaoui

Faraj

Pierra

et al. 1996

Antivir Chem Chemother

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Various purine β-L-2′,3′-dideoxynucleoside analogues with both sugar and base modifications including β-L-ddG, β-L-ddl, β-L-ddA, 2′-azido-β-L-araddA, 2′-amino-β-L-araddA, 2′,5′-anhydro-β-L-araddA, 2′-azido-β-L-ddA, 2′-amino-β-L-ddA, 2′-fluoro-β-L-ddA, 3′-azido-β-L-ddA, 3′-amino-β-L-ddA, 3′-fluoro-β-L-ddA, 2,6-diamino-β-L-2′,3′-dideoxyfuranosylpurine, 6-cyclopropylamino-β-L-ddA, 2′-azido-6-N-triphenylphosphine-β-L-araddA, 2-amino-6-methylamino-β-L-2′,3′-dideoxyfuranosylpurine, 2-amino-6-cyclopropylamino-β-L-2′,3′-dideoxyfuranosylpurine, 2-amino-6-cyclopentylamino-β-L-2′,3′-dideoxyfuranosylpurine, 2′,3′-didehydro-β-L-ddA and 2′,3′-didehydro-6-N-triphenyl phosphine-β-L-ddA were synthesized and evaluated as potential inhibitors of hepatitis B virus (HBV) replication in HBV DNA-transfected human hepatoblastoma-derived Hep-G2 cells (2.2.15 cells). β-L-ddA, 2′-azido-β-L-ddA, 3′-azido-β-L-ddA, 2″,3′-didehydro-β-L-ddA (β-L-D4A) and a modified base of β-L-D4A, inhibited HBV replication in vitro. β-L-D4A was the more potent and selective antiHBV agent with a 50% effective concentration value of 0.1 μM and a selectivity index of 1800. On the basis of this finding, studies are in progress to synthesize new purine derivatives with the β-L unnatural configuration which hopefully will lead to identifying additional potent and highly selective anti-HBV agents.

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Inhibition of duck hepatitis B virus replication by purine 2′,3′-dideoxynucleosides

Cited by 48 publications

References 18 publications

Superinfection Exclusion in Duck Hepatitis B Virus Infection Is Mediated by the Large Surface Antigen

Superinfection Exclusion in Duck Hepatitis B Virus Infection Is Mediated by the Large Surface Antigen

Generation of Stable Cell Lines Expressing Lamivudine-Resistant Hepatitis B Virus for Antiviral-Compound Screening

Inhibition of Hepatitis B Virus Replication by Nucleoside Enantiomers of β-2′,3′-Dideoxypurine Analogues

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