Hepatitis B: New Approaches for Antiviral Chemotherapy

Locarnini, Stephen; Civitico, Gilda; Newbold, John E.

doi:10.1177/095632029600700201

Cited by 18 publications

(12 citation statements)

References 59 publications

(46 reference statements)

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“…9 This pool of transcriptional templates appears to be very stable and studies by Summers et al using the duck hepatitis B virus (DHBV), have shown that the level of viral cccDNA is regulated by the pre-S envelope proteins via negative feedback. 10 Thus, early in infection when there are low amounts of surface envelope proteins, mature nucleocapsids are shunted into the nucleus whereby the newly synthesized viral genome is converted into cccDNA.…”

Section: Regulation Of Hepadnaviral Cccdna: Role Of the Viral Envelopementioning

confidence: 99%

Hepatitis B virus mutants and fulminant hepatitis B: Fitness plus phenotype

Bartholomeusz

2001

Hepatology

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The human hepatitis B virus (HBV) is the smallest known double-stranded DNA virus of man that replicates its genome through a novel mechanism of reverse transcription using the RNA-replicative intermediate and the viral pregenomic RNA. 1 Viral pregenomic RNA is synthesized from molecules of covalently closed circular (ccc) DNA, the major transcriptional template of the virus, functioning as a viral minichromosome within the nucleus of infected cells. 2 The reverse transcriptase of HBV lacks a conventional proofreading function, which is found in higher-order polymerases and, not surprisingly then, HBV exhibits a mutation rate more than 10-fold higher than other DNA viruses. The rates for nucleotide substitutions vary depending on the stage of disease. The natural evolutionary rate for the HBV genome in chronic hepatitis B is approximately 1.4 to 3.2 ϫ 10 Ϫ5 substitutions/site/year, 3 whereas in the liver transplantation setting, it is almost 100-fold higher. 4 Longitudinal studies have shown that these HBV mutations are not distributed evenly over the entire genome but rather tend to cluster into mutational patterns in particular parts of the viral DNA; in particular, the basal core promoter (BCP), the precore region and the "a" determinant of the viral envelope. 5 Importantly, the type and number of mutations that accumulate in the HBV genome over time have been shown to be a marker of the duration and/or severity of the liver disease, or the type and intensity of the immune response. 5 The outcome of HBV infection depends on the interplay between the virus, the hepatocyte, and the host's immune response. 6 Under normal circumstances, HBV is not cytopathic and liver damage is the result of the host's immune response targeting infected hepatocytes. However, during special or unusual circumstances, HBV appears to be directly cytopathic for hepatocytes often causing unique histopathologic conditions such as fibrosing cholestatic hepatitis, which, before the advent of specific antiviral therapy, 7 was invariably fatal. The molecular virologic and cellular basis for fulminant hepatitis B (FHB) has been the focus of intensive investigation, but to date the results have been controversial. In the report by Kalinina et al. in this issue of HEPATOLOGY, the investigators, have provided the first evidence, using in vitro functional studies that mutations in the S gene of the HBV isolated at the time of FHB had caused a severe defect in viral particle secretion. Earlier studies from this group had shown that the infectious clones from the same samples exhibited enhanced replication levels. 8 The enhanced replication and the severe defect in viral particle secretion most likely contributed to the fulminant clinical course of recurrent HBV infection posttransplantation. The patient was also hepatitis B e antigen (HBeAg) negative. REGULATION OF HEPADNAVIRAL cccDNA: ROLE OF THE VIRAL ENVELOPEVirus persistence in infected cells during chronic infection depends on the maintenance of the HBV cccDNA pool. 9 This pool of transcript...

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Section: Regulation Of Hepadnaviral Cccdna: Role Of the Viral Envelopementioning

confidence: 99%

Hepatitis B virus mutants and fulminant hepatitis B: Fitness plus phenotype

Bartholomeusz

2001

Hepatology

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“…ETV and the other three other approved nucleoside analogs lamivudine (3TC), adefovir dipivoxil (ADV), and telbivudine also target the HBV polymerase (Pol), which is essential to viral replication. Pol is responsible for converting the plus-strand pre-genomic RNA into a partially double-stranded circular DNA genome during a multistep process (1)(2)(3). ETV-5Ј monophosphate is incorporated by HBV Pol resulting in inhibition of the protein-linked priming activity, the reverse transcription of the pre-genomic mRNA, and the DNA-directed DNA synthesis activities of HBV Pol (4).…”

Section: Entecavir (Etv)mentioning

confidence: 99%

Pre-steady-state Kinetic Studies Establish Entecavir 5′-Triphosphate as a Substrate for HIV-1 Reverse Transcriptase

Domaoal

McMahon

Thio

et al. 2008

Journal of Biological Chemistry

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The novel 2 -deoxyguanosine analog Entecavir (ETV) is a potent inhibitor of hepatitis B virus (HBV) replication and is recommended for treatment in human immunodeficiency virus type 1 (HIV-1) and HBV-co-infected patients because it had been reported that ETV is HBV-specific. Recent clinical observations, however, have suggested that ETV may indeed demonstrate anti-HIV-1 activity. To investigate this question at a molecular level, kinetic studies were used to examine the interaction of 5 -triphosphate form of ETV with wild type (WT) HIV-1 reverse transcriptase (RT) and the nucleoside reverse transcriptase inhibitor-resistant mutation M184V. Using single turnover kinetic assays, we found that HIV-1 WT RT and M184V RT could use the activated ETV triphosphate metabolite as a substrate for incorporation. The mutant displayed a slower incorporation rate, a lower binding affinity, and a lower incorporation efficiency with the 5 -triphosphate form of ETV compared with WT RT, suggesting a kinetic basis for resistance. Our results are supported by cell-based assays in primary human lymphocytes that show inhibition of WT HIV-1 replication by ETV and decreased susceptibility of the HIV-1 containing the M184V mutation. This study has important therapeutic implications as it establishes ETV as an inhibitor for HIV-1 RT and illustrates the mechanism of resistance by the M184V mutant.Entecavir (ETV) 2 is a guanosine nucleoside analogue approved for the treatment of chronic hepatitis B virus (HBV) infection. The 5Ј-triphosphate form of ETV (ETVTP) inhibits HBV polymerase. Similar to other nucleoside analogs, upon entry into the cell, metabolic activation of ETV requires phosphorylation by cellular kinases to generate the active triphosphate form of the drug. ETV and the other three other approved nucleoside analogs lamivudine (3TC), adefovir dipivoxil (ADV), and telbivudine also target the HBV polymerase (Pol), which is essential to viral replication. Pol is responsible for converting the plus-strand pre-genomic RNA into a partially double-stranded circular DNA genome during a multistep process (1-3). ETV-5Ј monophosphate is incorporated by HBV Pol resulting in inhibition of the protein-linked priming activity, the reverse transcription of the pre-genomic mRNA, and the DNA-directed DNA synthesis activities of HBV Pol (4).

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“…4,42 Cessation of therapy with nucleoside analogs, in particular, has usually resulted in reversion of viral replication to at least pretreatment rates-the relapse phenomenon, which is most probably caused by intracellular persistence of HBV CCC DNA 21,23,41 -and persistence of virus in nonhepatocyte reservoirs. 25,30 Nowak et al 41 recently calculated that, on the basis of estimates of rates of viral and hepatocyte turnover, 1 year of continuous treatment with an effective nucleoside analog such as 3TC could, at best, result in complete elimination of HBV, and even, at worst, could reduce the frequency of infected hepatocytes to about 8%.…”

Section: Discussionmentioning

confidence: 99%

“…This situation the PDH test system, particularly with DHBV covalently closed could be expected to mimic the in vivo end-of-treatment situation circular (CCC) DNA, the replicative species most resistant to when residual nucleoside analog and virus are both present and antiviral therapy. 4,21 ''rebound'' (i.e., resumption of viral replication to at least pretreatment levels) commonly occurs. 23 Uninfected PDH cultures were MATERIALS AND METHODS prepared as described above and allowed to attach overnight before exposure for 24 hours to halving dilutions of 3TC and PCV (alone Drugs and Chemicals.…”

Section: Moval Furthermore the Combination Was More Effective Inmentioning

confidence: 99%

“…PCV is thus far unique in its ability to supantibody was detected by enhanced chemiluminescence. The total drug press regeneration of viral CCC DNA, which is normally concentration in each case was 0.8 mmol/L; lanes 1 to 5 correspond to resistant to antiviral therapy; 4,23,24,25,41 however, the antiviral 3TC:PCV ratios of 4:1, 1:1, 1:4, 1:0, and 0:1, respectively, and lanes 6 and effects of PCV are tissue and cell-specific, 30 and elimination alone. Similarly, long-term use of 3TC alone is unlikely to chemiluminescence were analyzed by densitometry, and the data were used completely eliminate chronic HBV infection despite claims to plot the column graph, which compares the effects of various drug treatto the contrary.…”

Section: Aid Hepa 0039mentioning

confidence: 99%

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Synergistic inhibition of hepadnaviral replication by lamivudine in combination with penciclovirin vitro

1997

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HBV was interferon alfa, but both short-and long-term re-SEE EDITORIAL ON PAGE 234 sponses to interferon are generally poor, even in the most successful studies.2 Because the sequelae of uncontrolled HBV infection include chronic active hepatitis, cirrhosis, and Lamivudine ([-]-b-L-2,3-dideoxy-3-thiacytidine [3TC])primary hepatocellular carcinoma, 3 there is a clear need for and penciclovir (9-[2-hydroxy-1-(hydroxymethyl)ethoxythe development of more reliable chemotherapy. class of antiviral agent, were unsuccessful or were comproand PCV are deoxycytidine and deoxyguanosine analogs, remised by associated toxicity. 5,6 Recent renewed interest in spectively, and their modes of action and how they interact the potential of nucleoside analogs to control HBV has been are matters of both theoretical and practical interest. We comstimulated by two main factors: 1) the discovery that HBV pared the antiviral activities of 3TC and PCV alone and in replication entails an obligatory reverse-transcription step identified as specific inhibitors of HIV reverse transcription and in combination, the two nucleoside analogs acted synergistically over a wide range of clinically relevant concentra-have been generally accepted as potential anti-HBV agents, tions. Synergy between PCV and 3TC was also observed in but experience has shown that peculiarities of hepatocyte acutely infected cells and in ''washout'' experiments designed enzymology severely limit the number that are actually useful to assess the persistence of antiviral activity after drug re-in vivo. analog that lacks the 3 hydroxy group necessary for DNA chain extension and has a sulfur atom instead of the normal Chronic hepatitis B virus (HBV) infection has been esti-3 carbon in the pentose ring. After being identified as a mated to affect more than 350 million individuals worldwide, potent and selective inhibitor of HIV replication, 19,20 3TC and currently available hepatitis B surface antigen-con-was approved for compassionate use as an anti-HIV agent. 11,15 taining vaccines are of no benefit to those individuals who Subsequently, 3TC was found to inhibit HBV replication in are already persistently infected with HBV and who consti-human hepatoma cells in vitro, 15 in patients coinfected with tute the major reservoir of potentially infectious virus.

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Hepatitis B: New Approaches for Antiviral Chemotherapy

Cited by 18 publications

References 59 publications

Hepatitis B virus mutants and fulminant hepatitis B: Fitness plus phenotype

Hepatitis B virus mutants and fulminant hepatitis B: Fitness plus phenotype

Pre-steady-state Kinetic Studies Establish Entecavir 5′-Triphosphate as a Substrate for HIV-1 Reverse Transcriptase

Synergistic inhibition of hepadnaviral replication by lamivudine in combination with penciclovirin vitro

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