Effects of mutations within and adjacent to the terminal repeats of hepatitis B virus pregenomic RNA on viral DNA synthesis.

1997 ◽  
Vol 71 (11) ◽  
pp. 8448-8455 ◽  
Author(s):  
S Perri ◽  
D Ganem
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Dna Synthesis ◽  
Viral Dna ◽  
B Virus ◽  
Terminal Repeats

scholarly journals Dominant negative mutants of the duck hepatitis B virus core protein interfere with RNA pregenome packaging and viral DNA synthesis

Hepatology ◽  
1999 ◽  
Vol 30 (1) ◽  
pp. 308-315 ◽  
Author(s):  
Fritz von Weizsäcker ◽  
Josef Köck ◽  
Stefan Wieland ◽  
Wolf-Bernhard Offensperger ◽  
Hubert E. Blum
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Dna Synthesis ◽  
Core Protein ◽  
Dominant Negative ◽  
Viral Dna ◽  
Duck Hepatitis B Virus ◽  
Virus Core ◽  
Duck Hepatitis ◽  
B Virus

scholarly journals Inhibition of hepatitis B virus by a novel L-nucleoside, 2'-fluoro-5-methyl-beta-L-arabinofuranosyl uracil.

1996 ◽  
Vol 40 (2) ◽  
pp. 380-386 ◽  
Author(s):  
S Balakrishna Pai ◽  
S H Liu ◽  
Y L Zhu ◽  
C K Chu ◽  
Y C Cheng
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Dna Synthesis ◽  
Hepg2 Cells ◽  
Inhibitory Concentration ◽  
Viral Dna ◽  
B Virus ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Dose Dependent

2'-Fluoro-5-methyl-beta-L-arabinofuranosyl uracil (L-FMAU) was discovered to have potent antiviral activity against hepatitis B virus (HBV). L-FMAU was more potent than its D-enantiomer and produced dose-dependent inhibition of the viral DNA replication in 2.2.15 cells (human HepG2 cells with the HBV genome), with a 50% inhibitory concentration of 0.1 microM. There was no inhibitory effect on HBV transcription or protein synthesis. In the 2.2.15 cell system, L-FMAU did not show any toxicity up to 200 microM, whereas the D-enantiomer was toxic, with a 50% inhibitory concentration of 50 microM. Repeated treatments of HepG2 cells with L-FMAU at a 1 microM concentration for 9 days did not result in any decrease in the total mitochondrial DNA content, suggesting that a mode of toxicity similar to that produced by 2',3'-dideoxycytidine is unlikely. Also at concentrations as high as 200 microM, L-FMAU did not adversely affect mitochondrial function as determined by lactic acid production by L-FMAU-treated hepatoma cells. L-FMAU was metabolized in the cells to its mono-, di-, and triphosphates, A dose-dependent inhibition of HBV DNA synthesis by L-FMAU triphosphate was observed in the DNA polymerase assays with isolated HBV particles, suggesting that the mode of action of this compound could involve viral polymerase. However, L-FMAU was not incorporated into the cellular DNA. Considering the potent inhibition of the viral DNA synthesis and the nontoxicity of L-FMAU towards the host DNA synthetic machinery, this compound should be further explored for development as asn anti-HBV drug.

scholarly journals Residues Arg703, Asp777, and Arg781 of the RNase H Domain of Hepatitis B Virus Polymerase Are Critical for Viral DNA Synthesis

2013 ◽  
Vol 88 (1) ◽  
pp. 154-163 ◽  
Author(s):  
C. Ko ◽  
Y.-C. Shin ◽  
W.-J. Park ◽  
S. Kim ◽  
J. Kim ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Dna Synthesis ◽  
Rnase H ◽  
Viral Dna ◽  
B Virus

scholarly journals Duck Hepatitis B Virus Nucleocapsids Formed by N-Terminally Extended or C-Terminally Truncated Core Proteins Disintegrate during Viral DNA Maturation

1998 ◽  
Vol 72 (11) ◽  
pp. 9116-9120 ◽  
Author(s):  
Josef Köck ◽  
Stefan Wieland ◽  
Hubert E. Blum ◽  
Fritz von Weizsäcker
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Dna Synthesis ◽  
Core Protein ◽  
Viral Dna ◽  
Duck Hepatitis B Virus ◽  
Duck Hepatitis ◽  
Core Proteins ◽  
B Virus ◽  
Carboxy Terminal

ABSTRACT Hepadnaviruses are DNA viruses that replicate through reverse transcription of an RNA pregenome. Viral DNA synthesis takes place inside viral nucleocapsids, formed by core protein dimers. Previous studies have identified carboxy-terminal truncations of the core protein that affect viral DNA maturation. Here, we describe the effect of small amino-terminal insertions into the duck hepatitis B virus (DHBV) core protein on viral DNA replication. All insertion mutants formed replication-competent nucleocapsids. Elongation of viral DNA, however, appeared to be incomplete. Increasing the number of additional amino acids and introducing negatively charged residues further reduced the observed size of mature viral DNA species. Mutant core proteins did not inhibit the viral polymerase. Instead, viral DNA synthesis destabilized mutant nucleocapsids, rendering mature viral DNA selectively sensitive to nuclease action. Interestingly, the phenotype of two previously described carboxy-terminal DHBV core protein deletion mutants was found to be based on the same mechanism. These data suggest that (i) the amino- as well as the carboxy-terminal portion of the DHBV core protein plays a critical role in nucleocapsid stabilization, and (ii) the hepadnavirus polymerase can perform partial second-strand DNA synthesis in the absence of intact viral nucleocapsids.

scholarly journals Inhibitory Effect of Adefovir on Viral DNA Synthesis and Covalently Closed Circular DNA Formation in Duck Hepatitis B Virus-Infected Hepatocytes In Vivo and In Vitro

2002 ◽  
Vol 46 (2) ◽  
pp. 425-433 ◽  
Author(s):  
Julien Delmas ◽  
Olivier Schorr ◽  
Catherine Jamard ◽  
Craig Gibbs ◽  
Christian Trépo ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Dna Synthesis ◽  
Dna Amplification ◽  
Viral Dna ◽  
Circular Dna ◽  
Covalently Closed Circular Dna ◽  
B Virus

ABSTRACT The elimination of viral covalently closed circular DNA (CCC DNA) from the nucleus of infected hepatocytes is an obstacle to achieving sustained viral clearance during antiviral therapy of chronic hepatitis B virus (HBV) infection. The aim of our study was to determine whether treatment with adefovir, a new acyclic nucleoside phosphonate, the prodrug of which, adefovir dipivoxil, is in clinical evaluation, is able to suppress viral CCC DNA both in vitro and in vivo using the duck HBV (DHBV) model. First, the effect of adefovir on viral CCC DNA synthesis was examined with primary cultures of DHBV-infected fetal hepatocytes. Adefovir was administered for six consecutive days starting one day before or four days after DHBV inoculation. Dose-dependent inhibition of both virion release in culture supernatants and synthesis of intracellular viral DNA was observed. Although CCC DNA amplification was inhibited by adefovir, CCC DNA was not eliminated by antiviral treatment and the de novo formation of CCC DNA was not prevented by pretreatment of the cells. Next, preventive treatment of experimentally infected ducklings with lamivudine or adefovir revealed that both efficiently suppressed viremia and intrahepatic DNA. However, persistence of viral DNA even when detectable only by PCR was associated with a recurrence of viral replication following drug withdrawal. Taken together, our results demonstrate that adefovir is a potent inhibitor of DHBV replication that inhibits CCC DNA amplification but does not effectively prevent the formation of CCC DNA from incoming viral genomes.

scholarly journals Noncompetitive Inhibition of Hepatitis B Virus Reverse Transcriptase Protein Priming and DNA Synthesis by the Nucleoside Analog Clevudine

2013 ◽  
Vol 57 (9) ◽  
pp. 4181-4189 ◽  
Author(s):  
Scott A. Jones ◽  
Eisuke Murakami ◽  
William Delaney ◽  
Phillip Furman ◽  
Jianming Hu
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Reverse Transcriptase ◽  
Dna Synthesis ◽  
Viral Dna ◽  
Second Stage ◽  
Chronic Hepatitis B Virus ◽  
B Virus ◽  
Tenofovir Df ◽  
Protein Priming

ABSTRACTAll currently approved antiviral drugs for the treatment of chronic hepatitis B virus (HBV) infection are nucleos(t)ide reverse transcriptase inhibitors (NRTI), which inhibit the DNA synthesis activity of the HBV polymerase. The polymerase is a unique reverse transcriptase (RT) that has a novel protein priming activity in which HP initiates viral DNA synthesis using itself as a protein primer. We have determined the ability of NRTI-triphosphates (TP) to inhibit HBV protein priming and their mechanisms of action. While entecavir-TP (a dGTP analog) inhibited protein priming initiated specifically with dGTP, clevudine-TP (a TTP analog) was able to inhibit protein priming independently of the deoxynucleoside triphosphate (dNTP) substrate and without being incorporated into DNA. We next investigated the effect of NRTIs on the second stage of protein priming, wherein two dAMP nucleotides are added to the initial deoxyguanosine nucleotide. The obtained results indicated that clevudine-TP as well as tenofovir DF-DP strongly inhibited the second stage of protein priming. Tenofovir DF-DP was incorporated into the viral DNA primer, whereas clevudine-TP inhibited the second stage of priming without being incorporated. Finally, kinetic analyses using the HBV endogenous polymerase assay revealed that clevudine-TP inhibited DNA chain elongation by HP in a noncompetitive manner. Thus, clevudine-TP appears to have the unique ability to inhibit HBV RT via binding to and distorting the HP active site, sharing properties with both NRTIs and nonnucleoside RT inhibitors.

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