The Experts below are selected from a list of 294 Experts worldwide ranked by ideXlab platform
Allison R Jilbert - One of the best experts on this subject based on the ideXlab platform.
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<B>DuckB> <B>HepatitisB> B virus covalently closed circular dna appears to survive hepatocyte mitosis in the growing liver
Virology, 2013Co-Authors: Georget Y Reaichemiller, William S Mason, Michael Thorpe, Huey Chi Low, Qiao Qiao, Catherine A Scougall, Samuel Litwin, Allison R JilbertAbstract:Nucleos(t)ide analogues that inhiBit <B>HepatitisB> B virus (HBV) DNA replication are typically used as monotherapy for chronically infected patients. Treatment with a nucleos(t)ide analogue eliminates most HBV DNA replication intermediates and produces a gradual decline in levels of covalently closed circular DNA (cccDNA), the template for viral RNA synthesis. It remains uncertain if levels of cccDNA decline primarily through hepatocyte death, or if loss also occurs during hepatocyte mitosis. To determine if cccDNA survives mitosis, growing <B>DuckB>lings infected with <B>DuckB> <B>HepatitisB> B virus (DHBV) were treated with the nucleoside analogue, Entecavir. Viremia was suppressed at least 10{sup 5}-fold, during a period when average liver mass increased 23-fold. Analysis of the data suggested that if cccDNA synthesis was completely inhiBited, at least 49% of cccDNA survived hepatocyte mitosis. However, there was a large <B>DuckB>-to-<B>DuckB> variation in cccDNA levels, suggesting that low level cccDNA synthesis may contriBute to this apparent survival through mitosis. - Highlights: • The <B>HepatitisB> B virus nuclear template is covalently closed circular DNA (cccDNA). • cccDNA was studied during liver growth in <B>DuckB> <B>HepatitisB> B virus infected <B>DuckB>s. • Virus DNA replication and new cccDNA synthesis were inhiBited with Entecavir. • At least 49% of cccDNA appeared tomore » survive hepatocyte mitosis. • Low level virus DNA synthesis may contriBute to survival of cccDNA through mitosis.« less
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nucleic acid polymers inhiBit <B>DuckB> <B>HepatitisB> B virus infection in vitro
Antimicrobial Agents and Chemotherapy, 2013Co-Authors: F Noordeen, Andrew Vaillant, Allison R JilbertAbstract:Nucleic acid polymers (NAPs) utilize the sequence-independent properties of phosphorothioate oligonucleotides (PS-ONs) to target protein interactions involved in viral replication. NAPs are Broadly active against a diverse range of enveloped viruses that use type I entry mechanisms. The antiviral activity of NAPs against <B>HepatitisB> B virus (HBV) infection was assessed in vitro in <B>DuckB> <B>HepatitisB> B virus (DHBV)-infected primary <B>DuckB> hepatocytes (PDH). NAPs efficiently entered PDH in the aBsence of any transfection agent and displayed antiviral activity at concentrations of 0.01 to 10 μM, measured By their aBility to prevent the intracellular accumulation of DHBV surface antigen, which was independent of their nucleotide sequence and was specifically dependent on phosphorothioation. Higher levels of antiviral activity were oBserved with NAPs 40 nucleotides in length or longer. The fully degenerate NAP (REP 2006) was active during DHBV infection or when added 12 h after infection. In contrast, an acidic-pH-sensitive NAP (REP 2031) that was Broadly active against other viruses displayed antiviral activity when present during DHBV infection But no activity when added 12 h after infection, suggesting that NAPs exert their postentry effect in an acidic environment unique to DHBV infection. Both REP 2006 and REP 2031 displayed negligiBle cytotoxicity in PDH at concentrations of up to 10 μM, as assessed using an XTT [2,3-Bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carBoxanilide] cytotoxicity assay. The antiviral activity of NAPs against DHBV in vitro was strictly dependent on their amphipathic character, suggesting that NAPs interact with amphipathic target(s) that are important for DHBV entry and postentry mechanisms required for infection.
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nucleic acid polymers prevent the estaBlishment of <B>DuckB> <B>HepatitisB> B virus infection in vivo
Antimicrobial Agents and Chemotherapy, 2013Co-Authors: F Noordeen, Andrew Vaillant, Allison R JilbertAbstract:Nucleic acid polymers (NAPs) are novel, Broad-spectrum antiviral compounds that use the sequence-independent properties of phosphorothioate oligonucleotides (PS-ONs) as amphipathic polymers to Block amphipathic interactions involved in viral entry. Using the <B>DuckB> <B>HepatitisB> B virus (DHBV) model of human <B>HepatitisB> B virus infection, NAPs have Been shown to have Both entry and postentry antiviral activity against DHBV infection in vitro in primary <B>DuckB> hepatocytes (PDH). In the current study, various NAPs were assessed for their prophylactic activity in vivo against DHBV infection in <B>DuckB>s. The degenerate NAP REP 2006 prevented the development of widespread and persistent DHBV infection in 14-day-old <B>DuckB>s, while the acidic-pH-sensitive NAP REP 2031 had little or no prophylactic effect. REP 2006 displayed significant toxicity in <B>DuckB>s, which was attriButed to CpG-mediated proinflammation, while REP 2031 (which has no CpG motifs) displayed no toxicity. A third NAP, REP 2055, which was designed to retain amphipathic activity at acidic pH and contained no CpG motifs, was well tolerated and displayed prophylactic activity against DHBV infection at doses as low as 1 mg/kg of Body weight/day. These studies suggest that NAPs can Be easily and predictaBly tailored to retain anti-DHBV activity and to have minimal toxic effects in vivo. Future studies are planned to estaBlish the therapeutic efficacy of NAPs against persistent DHBV infection.
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the development of persistent <B>DuckB> <B>HepatitisB> B virus infection can Be prevented using antiviral therapy comBined with dna or recomBinant fowlpoxvirus vaccines
Vaccine, 2010Co-Authors: Feng Feng, Qiao Qiao, Chee Quin Teoh, David L Boyle, Allison R JilbertAbstract:We recently reported the development of a successful post-exposure comBination antiviral and "prime-Boost" vaccination strategy using the <B>DuckB> <B>HepatitisB> B virus (DHBV) model of human <B>HepatitisB> B virus infection. The current study aimed to simplify the vaccination strategy and to test the post-exposure efficacy of comBination therapy with the Bristol-Myers SquiBB antiviral drug, entecavir (ETV) and either a single dose of DHBV DNA vaccines on day 0 post-infection (p.i.) or a single dose of recomBinant fowlpoxvirus (rFPV-DHBV) vaccines on day 7 p.i. Whilst untreated control <B>DuckB>s infected with an equal dose of DHBV all developed persistent and wide spread DHBV infection of the liver, <B>DuckB>s treated with ETV comBined with either the DHBV DNA vaccines on day 0 p.i. or the rFPV-DHBV vaccines on day 7 p.i. had no detectaBle DHBV-infected hepatocytes By day 14 p.i. and were protected from the development of persistent DHBV infection.
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the persistence in the liver of residual <B>DuckB> <B>HepatitisB> B virus covalently closed circular dna is not dependent upon new viral dna synthesis
Virology, 2010Co-Authors: Georget Y Reaiche, William S Mason, Marc Le F Mire, Allison R JilbertAbstract:Residual <B>HepatitisB> B virus (HBV) DNA can Be detected following the resolution of acute HBV infection. Our previous work using <B>DuckB> <B>HepatitisB> B virus (DHBV) infected <B>DuckB>s, indicated that ~80% of residual DHBV DNA in the liver is in the covalently closed circular DNA (cccDNA) form, suggesting that viral DNA synthesis is suppressed. The current study asked more directly if maintenance of residual DHBV cccDNA is dependent upon ongoing viral DNA synthesis. <B>DuckB>s that recovered from acute DHBV infection were divided into 2 groups and treated with the antiviral drug, Entecavir (ETV), or placeBo. No major differences in the staBility of cccDNA or levels of residual cccDNA were oBserved in liver Biopsy tissues taken 95 days apart from ETV treated and placeBo control <B>DuckB>s. The data suggest that residual DHBV cccDNA is highly staBle and present in a cell population with a rate of turnover similar to normal, uninfected hepatocytes.
John E Tavis - One of the best experts on this subject based on the ideXlab platform.
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rna elements directing translation of the <B>DuckB> <B>HepatitisB> B virus polymerase via riBosomal shunting
Journal of Virology, 2011Co-Authors: Feng Cao, John E TavisAbstract:The <B>DuckB> <B>HepatitisB> B virus (DHBV) reverse transcriptase (P) is translated from the downstream position on a Bicistronic mRNA, called the pregenomic RNA, through a poorly characterized riBosomal shunt. Here, the positions of the discontinuous riBosomal transfer during shunting were mapped, and RNA elements important for shunting were identified as a prelude to dissecting the shunting mechanism. Mutations were introduced into the DHBV genome, genomic expression vectors were transfected into cells which support reverse transcription, and P translation efficiency was defined as the ratio of P/mRNA. Five oBservations were made. First, riBosomes departed from sequences that comprise the RNA stem-loop called e that is key to viral replication, But the known elements of e were not needed for shunting. Second, at least two landing sites for riBosomes were found on the mRNA. Third, all sequences upstream of e, most sequences Between the cap and the P AUG, and sequences within the P-coding region were dispensaBle for shunting. Fourth, elements on the mRNA involved in reverse transcription or predicted to Be involved in shunting on the Basis of mechanisms documented in other viruses, including short open reading frames near the departure site, were not essential for shunting. Finally, two RNA elements in the 5′ portion of the mRNA were found to assist shunting. These oBservations are most consistent with shunting Being directed By signals that act through an uncharacterized RNA secondary structure. Together, these data indicate that DHBV employs either a novel shunting mechanism or a major variation on one of the characterized mechanisms.
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the <B>DuckB> <B>HepatitisB> B virus reverse transcriptase functions as a full length monomer
Journal of Biological Chemistry, 2006Co-Authors: Zhian Zhang, John E TavisAbstract:Hepadnaviral reverse transcription occurs within cytoplasmic capsid particles and is catalyzed By a virally encoded reverse transcriptase, But the primary structure and multimeric state of the polymerase during reverse transcription are poorly understood. We measured these parameters for the <B>DuckB> <B>HepatitisB> B virus polymerase employing active enzyme translated in vitro and derived from intracellular core particles and mature virions. In vitro-translated polymerase immunoprecipitated as a monomer, and polymerase molecules with complementary defects in the enzymatic active site and tyrosine 96, which primes DNA synthesis, could not complement or inhiBit each other in priming assays. Western analysis using antiBodies recognizing epitopes throughout the polymerase comBined with nuclease digestion of permeaBilized virion-derived capsid particles revealed that only full-length polymerase molecules were in virions and that they were all covalently attached to large DNA molecules. Because DNA synthesis is primed By the polymerase itself and only one copy of the viral DNA is in each capsid, the polymerase must function as an uncleaved monomer. Therefore, a single polymerase monomer is encapsidated, primes DNA synthesis, synthesizes Both DNA strands, and participates in the three-strand transfers of DNA synthesis, with all steps after DNA priming performed while the polymerase is covalently coupled to the product DNA. Because the N-terminal domain of the polymerase is displaced from the active site on the same molecule By the viral DNA during reverse transcription, P must Be structurally dynamic during DNA synthesis. Therefore, non-nucleoside compounds that interfere with this change may Be novel antiviral agents.
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identification of an essential molecular contact point on the <B>DuckB> <B>HepatitisB> B virus reverse transcriptase
Journal of Virology, 2005Co-Authors: Feng Cao, Matthew P Badtke, Lisa M Metzger, Ermei Yao, Babatunde Adeyemo, Yunhao Gong, John E TavisAbstract:The hepadnaviral polymerase (P) functions in a complex with viral nucleic acids and cellular chaperones. To Begin to identify contacts Between P and its partners, we assessed the exposure of the epitopes of six monoclonal antiBodies (MABs) to the terminal protein domain of the <B>DuckB> <B>HepatitisB> B virus P protein in a partially denaturing Buffer (RIPA) and a physiological Buffer (IPP150). All MABs immunoprecipitated in vitro translated P well in RIPA, But three immunoprecipitated P poorly in IPP150. Therefore, the epitopes for these MABs were oBscured in the native conformation of P But were exposed when P was in RIPA. Epitopes for MABs that immunoprecipitated P poorly in IPP150 were Between amino acids (aa) 138 and 202. Mutation of a highly conserved motif within this region (T3; aa 176 to 183) improved the immunoprecipitation of P By these MABs and simultaneously inhiBited DNA priming By P. Peptides containing the T3 motif inhiBited DNA priming in a dose-dependent manner, whereas eight irrelevant peptides did not. T3 function appears to Be conserved among the hepadnaviruses Because mutating T3 aBlated DNA synthesis in Both <B>DuckB> <B>HepatitisB> B virus and <B>HepatitisB> B virus. These results indicate that (i) the conserved T3 motif is a molecular contact point whose ligand can Be competed By soluBle T3 peptides, (ii) the occupancy of T3 oBscures the epitopes for three MABs, and (iii) proper occupancy of T3 By its ligand is essential for DNA priming. Therefore, small-molecule ligands that compete for Binding to T3 with its natural ligand could form a novel class of antiviral drugs.
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kinetics of synthesis and turnover of the <B>DuckB> <B>HepatitisB> B virus reverse transcriptase
Journal of Biological Chemistry, 2003Co-Authors: Ermei Yao, John E TavisAbstract:Hepadnaviral reverse transcription occurs in suBviral capsids in which the core protein surrounds the reverse transcriptase ("polymerase") and the pregenomic RNA. The pregenomic RNA is the template for reverse transcription and also the Bicistronic mRNA for core and polymerase. The pregenomic RNA structure and the capsid stoichiometry imply that vastly more core would Be translated than polymerase. Previously, we found that <B>DuckB> <B>HepatitisB> B virus polymerase unexpectedly accumulates in the cytoplasm (Yao, E., Gong, Y., Chen, N., and Tavis, J. E. (2000) J. Virol. 74, 8648-8657). The production mechanism and function of the excess polymerase are unknown. Here, we determined the kinetics of expression and degradation of polymerase and core in cells producing virus. Polymerase was translated 10% as rapidly as core, the half-life of nonencapsidated polymerase was very short, core had a very long half-life, and very few polymerase molecules were encapsidated. The presence of excess polymerase indicates that the translation rate of the polymerase is not limiting for encapsidation. Therefore, encapsidation must Be regulated By other events, most likely Binding of the polymerase to the pregenomic RNA. These data support the hypothesis that polymerase may have functions Beyond copying the viral genome By demonstrating that the polymerase is a cytoplasmic protein that is only rarely encapsidated.
Yongyuan Zhang - One of the best experts on this subject based on the ideXlab platform.
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RESEARCH ARTICLE <B>DuckB> <B>HepatitisB> B Virus cccDNA Amplification Efficiency in Natural Infection Is Regulated By Virus Secretion Efficiency
2016Co-Authors: Yongyuan ZhangAbstract:Previous mutation Based studies showed that aBlating synthesis of viral envelope proteins led to elevated hepadnaviral covalently closed circular DNA (cccDNA) amplification, But it remains unknown how cccDNA amplification is regulated in natural hepadnaviral infection Because of a lack of research system. In this study we report a simple procedure to prepare two identical <B>DuckB> <B>HepatitisB> B virus inocula, But they possess 10-100-fold difference in cccDNA amplification in infected cell culture. We demonstrate that the infected cells with higher cccDNA amplification significantly reduce the virus secretion efficiency that results in higher accumulation of relaxed circular DNA (rcDNA) and DHBsAg in the cells. The infected cells with lower cccDNA amplification significantly increase the virus secretion efficiency that leads to lower intracellular rcDNA and DHBsAg accumulation. In contrast with the findings generated in the mutation Based experimental system, the regulation of cccDNA amplification in natural hepadnaviral infection Bypasses direct regulation of the cellular envelope proteins concentration, instead it modulates virus secretion efficiency that ulti-mately impacts the intracellular rcDNA concentration, an important factor determining the destination of the synthesized rcDNA in infected cells
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<B>DuckB> <B>HepatitisB> B virus cccdna amplification efficiency in natural infection is regulated By virus secretion efficiency
PLOS ONE, 2015Co-Authors: Yongyuan ZhangAbstract:Previous mutation Based studies showed that aBlating synthesis of viral envelope proteins led to elevated hepadnaviral covalently closed circular DNA (cccDNA) amplification, But it remains unknown how cccDNA amplification is regulated in natural hepadnaviral infection Because of a lack of research system. In this study we report a simple procedure to prepare two identical <B>DuckB> <B>HepatitisB> B virus inocula, But they possess 10-100-fold difference in cccDNA amplification in infected cell culture. We demonstrate that the infected cells with higher cccDNA amplification significantly reduce the virus secretion efficiency that results in higher accumulation of relaxed circular DNA (rcDNA) and DHBsAg in the cells. The infected cells with lower cccDNA amplification significantly increase the virus secretion efficiency that leads to lower intracellular rcDNA and DHBsAg accumulation. In contrast with the findings generated in the mutation Based experimental system, the regulation of cccDNA amplification in natural hepadnaviral infection Bypasses direct regulation of the cellular envelope proteins concentration, instead it modulates virus secretion efficiency that ultimately impacts the intracellular rcDNA concentration, an important factor determining the destination of the synthesized rcDNA in infected cells.
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age related differences in amplification of covalently closed circular dna at early times after <B>DuckB> <B>HepatitisB> B virus infection of <B>DuckB>s
Journal of Virology, 2005Co-Authors: Yongyuan Zhang, Daniel Theele, Jesse SummersAbstract:Inoculation of 3-day-old (3D) or 3-week-old (3W) <B>DuckB>lings with <B>DuckB> <B>HepatitisB> B virus results in chronic or transient infection, respectively. We previously showed that rapid production of neutralizing antiBody following inoculation of 3W <B>DuckB>lings prevents virus from spreading in the liver and leads to a transient infection (Y.-Y. Zhang and J. Summers, J. Virol. 78:1195-1201, 2004). In this study we further investigated early events of viral infection in Both 3D and 3W <B>DuckB>s. We present evidence that a lower level of virus replication in the hepatocytes of 3W Birds is an additional factor that proBaBly favors transient infection. We suggest that lower virus replication is due to a less rapid covalently closed circular DNA amplification, leading to lower viremias and a slower spread of infection in the liver, and that the slower spread of infection in 3W <B>DuckB>s makes the infection more sensitive to interruption By the host immune responses.
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enrichment of a precore minus mutant of <B>DuckB> <B>HepatitisB> B virus in experimental mixed infections
Journal of Virology, 1999Co-Authors: Yongyuan Zhang, Jesse SummersAbstract:A precore-deficient mutant of <B>DuckB> <B>HepatitisB> B virus (DHBV) produced By site-directed mutagenesis was tested for its aBility to compete with wild-type virus in a mixed infection of 3-day-old <B>DuckB>lings. The mutation was shown to produce a cis-acting defect, resulting in a replication rate that was aBout one-half that of wild-type virus. Accordingly, wild-type virus was rapidly selected during the spread of infection. During the chronic phase of the infection, however, two selection patterns were seen. In 4 of 10 <B>DuckB>s, the wild-type virus slowly replaced the precore mutant. In another four <B>DuckB>s, the precore mutant virus slowly replaced the wild-type virus. In the remaining two <B>DuckB>lings, ratios of wild-type and precore mutant virus fluctuated, with wild-type virus slowly predominating. The replacement of wild-type virus was not due to the emergence of a rapidly replicating variant of the precore mutant, since genomes cloned from the infected <B>DuckB>s retained their original replication defect. Replacement of wild-type virus, however, correlated with elevated anti-core antiBody titers, which continued to increase with time. The selection of a precore-negative strain of DHBV may Be analogous to the selection for precore mutants of HBV during chronic <B>HepatitisB> in humans.
William S Mason - One of the best experts on this subject based on the ideXlab platform.
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<B>DuckB> <B>HepatitisB> B virus covalently closed circular dna appears to survive hepatocyte mitosis in the growing liver
Virology, 2013Co-Authors: Georget Y Reaichemiller, William S Mason, Michael Thorpe, Huey Chi Low, Qiao Qiao, Catherine A Scougall, Samuel Litwin, Allison R JilbertAbstract:Nucleos(t)ide analogues that inhiBit <B>HepatitisB> B virus (HBV) DNA replication are typically used as monotherapy for chronically infected patients. Treatment with a nucleos(t)ide analogue eliminates most HBV DNA replication intermediates and produces a gradual decline in levels of covalently closed circular DNA (cccDNA), the template for viral RNA synthesis. It remains uncertain if levels of cccDNA decline primarily through hepatocyte death, or if loss also occurs during hepatocyte mitosis. To determine if cccDNA survives mitosis, growing <B>DuckB>lings infected with <B>DuckB> <B>HepatitisB> B virus (DHBV) were treated with the nucleoside analogue, Entecavir. Viremia was suppressed at least 10{sup 5}-fold, during a period when average liver mass increased 23-fold. Analysis of the data suggested that if cccDNA synthesis was completely inhiBited, at least 49% of cccDNA survived hepatocyte mitosis. However, there was a large <B>DuckB>-to-<B>DuckB> variation in cccDNA levels, suggesting that low level cccDNA synthesis may contriBute to this apparent survival through mitosis. - Highlights: • The <B>HepatitisB> B virus nuclear template is covalently closed circular DNA (cccDNA). • cccDNA was studied during liver growth in <B>DuckB> <B>HepatitisB> B virus infected <B>DuckB>s. • Virus DNA replication and new cccDNA synthesis were inhiBited with Entecavir. • At least 49% of cccDNA appeared tomore » survive hepatocyte mitosis. • Low level virus DNA synthesis may contriBute to survival of cccDNA through mitosis.« less
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the persistence in the liver of residual <B>DuckB> <B>HepatitisB> B virus covalently closed circular dna is not dependent upon new viral dna synthesis
Virology, 2010Co-Authors: Georget Y Reaiche, William S Mason, Marc Le F Mire, Allison R JilbertAbstract:Residual <B>HepatitisB> B virus (HBV) DNA can Be detected following the resolution of acute HBV infection. Our previous work using <B>DuckB> <B>HepatitisB> B virus (DHBV) infected <B>DuckB>s, indicated that ~80% of residual DHBV DNA in the liver is in the covalently closed circular DNA (cccDNA) form, suggesting that viral DNA synthesis is suppressed. The current study asked more directly if maintenance of residual DHBV cccDNA is dependent upon ongoing viral DNA synthesis. <B>DuckB>s that recovered from acute DHBV infection were divided into 2 groups and treated with the antiviral drug, Entecavir (ETV), or placeBo. No major differences in the staBility of cccDNA or levels of residual cccDNA were oBserved in liver Biopsy tissues taken 95 days apart from ETV treated and placeBo control <B>DuckB>s. The data suggest that residual DHBV cccDNA is highly staBle and present in a cell population with a rate of turnover similar to normal, uninfected hepatocytes.
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characterization of the antiviral effects of 2 carBodeoxyguanosine in <B>DuckB>s chronically infected with <B>DuckB> <B>HepatitisB> B virus
Hepatology, 1994Co-Authors: William S Mason, John M Cullen, Jeff Saputelli, Chen Liu, Thomas W London, Edward D Lustbader, Priscilla A Schaffer, Anna Oconnell, Isabelle FourelAbstract:This study was carried out to evaluate Benefits and limitations of long-term therapy of <B>HepatitisB> B virus infections with a nucleoside analog inhiBitor of virus replication. The model we used was the domestic <B>DuckB> chronically infected with <B>DuckB> <B>HepatitisB> B virus By in ovo infection. 2′ CarBodeoxyguanosine was used as an inhiBitor of viral DNA synthesis. In all animals examined there was a reduction in virus production during therapy. A dose of 2′ carBodeoxyguanosine of 10 μg/kg every other day reduced the numBer of infected hepatocytes from greater than 95 to 25 to 50 in less than 3 mo, whereas a 10-fold higher dose produced a decline to less than 10. Histological evaluation revealed mild to moderate liver injury in <B>DuckB>s receiving the higher dose of 2′ carBodeoxyguanosine, suggesting that disappearance of infected hepatocytes may have Been accelerated By a toxic effect of the drug. Drug treatment did not completely eliminate <B>DuckB> <B>HepatitisB> B virus from any <B>DuckB>, and replication was restored in all hepatocytes within a few weeks to several months after antiviral therapy was terminated. Our results suggest that elimination of a chronic infection with a single inhiBitor of replication may Be difficult in a host that lacks an antiviral immune response capaBle of eliminating at least a portion of the infected hepatocytes and of ultimately producing antiBodies capaBle of neutralizing residual virus. (Hepatology 1994; 19:398–411).
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rapid resolution of <B>DuckB> <B>HepatitisB> B virus infections occurs after massive hepatocellular involvement
Journal of Virology, 1992Co-Authors: A R Jilbert, Anna Oconnell, J M England, P M Hall, N Z Carp, William S MasonAbstract:A study was carried out to determine some of the factors that might distinguish transient from chronic hepadnavirus infection. First, to Better characterize chronic infection, Pekin <B>DuckB>s, congenitally infected with the <B>DuckB> <B>HepatitisB> B virus (DHBV), were used to assess age-dependent variations in viremia, percentage of DHBV-infected hepatocytes, and average levels of DNA replication intermediates in the cytoplasm and of covalently closed circular DNA in the nuclei of infected hepatocytes. Levels of viremia and viral DNA were found to peak at aBout the time of hatching But persisted at relatively constant levels in chronically infected Birds up to 2 years of age. The percentage of infected hepatocytes was also constant, with DHBV replication in virtually 100% of hepatocytes in all Birds. Next, we found that adolescent <B>DuckB>s inoculated intravenously with a large dose of DHBV also developed massive infection of hepatocytes with an early But low-level viremia, followed By rapid development of a neutralizing antiBody response. No oBvious quantitative or qualitative differences Between transiently and chronically infected liver tissue were detected in the intracellular markers of viral replication examined. However, in the adolescent <B>DuckB> experiment, DHBV infection was rapidly cleared from the liver even when up to 80% of hepatocytes were initially infected. In all of these <B>DuckB>s, clearance of infection was accompanied By only a mild <B>HepatitisB>, with no evidence that massive cell death contriButed to the clearance. This finding suggested that mechanisms in addition to immune-mediated destruction of hepatocytes might make major contriButions to clearance of infections, including physiological turnover of hepatocytes in the presence of a neutralizing antiBody response and/or spontaneous loss of the capacity of hepatocytes to support virus replication.
Lucyna Cova - One of the best experts on this subject based on the ideXlab platform.
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enhancement of neutralizing humoral response of dna vaccine against <B>DuckB> <B>HepatitisB> B virus envelope protein By co delivery of cytokine genes
Vaccine, 2008Co-Authors: Fadi Saade, Thierry Buronfosse, Pierre Pradat, Fabien Abdul, Lucyna CovaAbstract:We explored in the <B>DuckB> <B>HepatitisB> B virus (DHBV) model the impact of <B>DuckB> interferon gamma (Du-IFNγ) or interleukin 2 (Du-IL2) co-delivery on humoral neutralizing response induced By DNA-Based vaccine encoding DHBV preS/S large envelope protein. Co-delivery of either Du-IL2 or DU-IFNγ encoding plasmids consideraBly increased the magnitude of anti-preS humoral response. Moreover, co-administration of cytokine genes led to a significant (p < 0.001) enhancement of neutralizing anti-DHBV antiBody response, which was more pronounced for Du-IFNγ. Our data suggest that co-delivery of cytokine and envelope protein encoding plasmids will Be a valuaBle approach for the development of a potent therapeutic DNA vaccine against chronic <B>HepatitisB> B.
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residues critical for <B>DuckB> <B>HepatitisB> B virus neutralization are involved in host cell interaction
Journal of Virology, 1999Co-Authors: Claire Sunyach, Hans Will, Christine S Rollier, M Robaczewska, Christelle Borel, Luc Barraud, Alan Kay, Christian Trepo, Lucyna CovaAbstract:To date, no detailed analysis of the neutralization properties of <B>DuckB> <B>HepatitisB> B virus (DHBV) has Been reported, and it is not clear whether any of the known neutralization epitopes correspond to the viral receptor Binding site or to sequences involved in the cell entry pathway. We demonstrate here that antiBodies directed against two overlapping peptides (amino acids 83 to 97 and 93 to 107), covering the sequences of most DHBV pre-S neutralizing epitopes, Both inhiBit virus Binding to primary <B>DuckB> hepatocytes and neutralize virus infectivity. An extensive mutagenesis of the motif 88WTP90, which is the shortest sequence of the epitope recognized By the virus-neutralizing monoclonal antiBody (MAB) 900 was performed in order to define the amino acids involved in these interactions. Single point mutations within this epitope affected neither virus replication nor infectivity But aBolished virus neutralization By MAB 900 completely. Interestingly, mutants with two and three consecutive residue replacements (SIP and SIH) within this epitope retained replication competence But were no longer infectious. The loss of infectivity of SIH and SIP mutant particles was associated with significantly reduced Binding to primary <B>DuckB> hepatocytes and could Be rescued By trans complementation with wild-type pre-S protein. Taken together, these results indicate that each amino acid of the DHBV pre-S sequence 88WTP90 is critical for recognition By the neutralizing MAB 900 and that replacement of the first two or all three residues strongly reduces virus interaction with hepatocytes and aBrogates infectivity. These data imply that the motif 88WTP90 contains key residues which are critical for interaction with Both the neutralizing MAB and the host cell.
