Long-term hepatitis B surface antigen (HBsAg) kinetics during nucleoside/nucleotide analogue therapy: Finite treatment duration unlikely

Chevaliez, Stéphane; Hézode, Christophe; Bahrami, Stéphane; Grare, Marion; Pawlotsky, Jean‐Michel

doi:10.1016/j.jhep.2012.11.039

Cited by 220 publications

(186 citation statements)

References 34 publications

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“…8). Completely purging cccDNA from a patient´s liver by this approach could take >50 y (62). Silencing the transcriptional activity of cccDNA (63) may suffer the same limitations.…”

Section: In-cell Evidence For Tdp2 Involvement In Hepadnaviral Cccdnamentioning

confidence: 99%

Involvement of the host DNA-repair enzyme TDP2 in formation of the covalently closed circular DNA persistence reservoir of hepatitis B viruses

Königer

Wingert

Marsmann

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

207

193

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Hepatitis B virus (HBV), the causative agent of chronic hepatitis B and prototypic hepadnavirus, is a small DNA virus that replicates by protein-primed reverse transcription. The product is a 3-kb relaxed circular DNA (RC-DNA) in which one strand is linked to the viral polymerase (P protein) through a tyrosyl-DNA phosphodiester bond. Upon infection, the incoming RC-DNA is converted into covalently closed circular (ccc) DNA, which serves as a viral persistence reservoir that is refractory to current anti-HBV treatments. The mechanism of cccDNA formation is unknown, but the release of P protein is one mandatory step. Structural similarities between RC-DNA and cellular topoisomerase-DNA adducts and their known repair by tyrosyl-DNA-phosphodiesterase (TDP) 1 or TDP2 suggested that HBV may usurp these enzymes for its own purpose. Here we demonstrate that human and chicken TDP2, but only the yeast ortholog of TDP1, can specifically cleave the Tyr-DNA bond in virus-adapted model substrates and release P protein from authentic HBV and duck HBV (DHBV) RC-DNA in vitro, without prior proteolysis of the large P proteins. Consistent with TPD2's having a physiological role in cccDNA formation, RNAi-mediated TDP2 depletion in human cells significantly slowed the conversion of RC-DNA to cccDNA. Ectopic TDP2 expression in the same cells restored faster conversion kinetics. These data strongly suggest that TDP2 is a first, although likely not the only, host DNA-repair factor involved in HBV cccDNA biogenesis. In addition to establishing a functional link between hepadnaviruses and DNA repair, our results open new prospects for directly targeting HBV persistence.hepatitis B virus persistence | TDP substrate specificity | virus-DNA repair interface M ore than 250 million people worldwide are chronically infected with hepatitis B virus (HBV) (1) and are at a highly increased risk for developing end-stage liver disease (2). Current treatments with IFN-α or nucleos(t)ide analogs (NAs) are only partially effective (3, 4). Importantly, they do not directly target the viral persistence reservoir, an episomal covalently closed circular (ccc) DNA form of the viral genome that serves as template for all viral transcripts; hence a few cccDNA molecules present in the liver can reactivate full viral replication. Eliminating infection thus will require the elimination of cccDNA. cccDNA is generated, upon infection, from the viral polymerase (P protein)-linked relaxed circular (RC) DNA present in incoming virions (Fig. 1A). The mechanism by which RC-DNA is converted to cccDNA is poorly understood, but it must involve multiple steps (see below). Because the ∼3-kb genomes of HBV and the other hepadnaviruses [e.g., from ducks (DHBV)] are too small to encode all the activities required for this conversion, these activities must be provided by the host cell.RC-DNA from all hepadnaviruses bears several molecular peculiarities that result from its generation by protein-primed reverse transcription (for reviews, see refs. 5 and 6). The pregenomic RNA (p...

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“…8). Completely purging cccDNA from a patient´s liver by this approach could take >50 y (62). Silencing the transcriptional activity of cccDNA (63) may suffer the same limitations.…”

Section: In-cell Evidence For Tdp2 Involvement In Hepadnaviral Cccdnamentioning

confidence: 99%

Involvement of the host DNA-repair enzyme TDP2 in formation of the covalently closed circular DNA persistence reservoir of hepatitis B viruses

Königer

Wingert

Marsmann

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

207

193

View full text Add to dashboard Cite

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“…Available therapies have modest curative efficacy and there is a need for development of new approaches to eliminating HBV from chronic carriers of the virus [2] and [3]. Central to the limitations of current treatments is the inability to eliminate the cccDNA from infected hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

“…It is estimated that 240 million people are chronic carriers of the virus and these individuals are at high risk for complicating cirrhosis and hepatocellular carcinoma. Currently licensed therapies for HBV infection include nucleoside analogs, nucleotide analogs and derivatives of interferon alpha (IFN-α) [2] and [3]. Although these therapies diminish replication of HBV, treatment interruption usually results in relapse with proliferation of the virus.…”

Section: Introductionmentioning

confidence: 99%

Improved antiviral efficacy using TALEN-mediated homology directed recombination to introduce artificial primary miRNAs into DNA of hepatitis B virus

Dreyer

Nicholson

Ely

et al. 2016

Biochemical and Biophysical Research Communications

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Highlights• Chronic infection with HBV is attributed to cccDNA persistence.• TALENs and miRNA activators have shown anti-HBV therapeutic promise.• HDR of HBV targets with TALENs and pri-miRNA donors augmented antiviral efficacy.• Combining gene editing and silencing improves inhibition of HBV gene expression. AbstractChronic infection with hepatitis B virus (HBV) remains an important global health problem. Currently licensed therapies have modest curative efficacy, which is as a result of their transient effects and limited action on the viral replication intermediate comprising covalently closed circular DNA (cccDNA). Gene editing with artificial HBV-specific endonucleases and use of artificial activators of the RNA interference pathway have shown anti-HBV therapeutic promise. Although results from these gene therapies are encouraging, maximizing durable antiviral effects is important. To address this goal, a strategy that entails combining gene editing with homology-directed DNA recombination (HDR), to introduce HBV-silencing artificial primary microRNAs (pri-miRs) into HBV DNA targets, is reported here. Previously described transcription activator-like effector nucleases (TALENs) that target the core and surface sequences of HBV were used to introduce double stranded breaks in the viral DNA. Simultaneous administration of donor sequences encoding artificial promoterless anti-HBV pri-miRs, with flanking arms that were homologous to sequences adjoining the TALENs' targets, augmented antiviral efficacy. Analysis showed targeted integration and the length of the flanking homologous arms of donor DNA had a minimal effect on antiviral efficiency. These results support the notion that gene editing and silencing may be combined to effect improved inhibition of HBV gene expression.

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“…Additionally, HBeAg that is negatively converted by NUC administration frequently re-appears when NUC administration is stopped (reverse seroconversion) [59,60] after a flare of severe hepatitis [61] . There have been several reports that NUC contributes to HBsAg-negative conversion [62][63][64][65] . To improve the longterm prognosis of patients, continuous administration of NUCs for long-term HBV suppression is necessary.…”

Section: Nucsmentioning

confidence: 99%

Current and future directions for treating hepatitis B virus infection

Tawada

Yokosuka

2015

WJH

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Hepatitis B virus (HBV) persistently infects approximately 350 million people, and approximately 600000 liverrelated deaths are observed per year worldwide. HBV infection is also one of the major risk factors for hepatocellular carcinoma (HCC). The persistence of serum hepatitis B e antigen (HBeAg) and high level of serum HBV DNA are thought to reflect a high HBV replication status in hepatocytes, causing cirrhosis, HCC and liver-related deaths. It has been reported that antiviral therapy, such as peginterferon and nucleos(t)ide analogues (NUCs), could suppress liver-related death by inhibiting the HBV DNA levels and inducing seroconversion from HBeAg to antibody to HBe antigen. Currently, peginterferon is widely used, but there are also several disadvantages in the use of peginterferon, such as various adverse events, the administration route and duration. It is difficult to predict the effects of treatment and interferon is contraindicated for the patients with advanced fibrosis of the liver and cirrhosis. With respect to NUCs, entecavir and tenofovir disoproxil fumarate are current the first-choice drugs. NUCs can be administered orally, and their anti-viral effects are stronger than that of peginterferon. However, because cessation of NUC administration leads to high levels of viral replication and causes severe hepatitis, they must be administered for a long time. On the other hand, the use of both interferon and NUCs cannot eliminate covalently closed circular DNA of HBV. In this review, we evaluate the natural course of chronic HBV infection and then provide an outline of these representative drugs, such as peginterferon, entecavir and tenofovir disoproxil fumarate.

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Long-term hepatitis B surface antigen (HBsAg) kinetics during nucleoside/nucleotide analogue therapy: Finite treatment duration unlikely

Abstract: Long-term hepatitis B surface antigen (HBsAg) kinetics during nucleoside/nucleotide analogue therapy: Finite treatment duration unlikely

Cited by 220 publications

References 34 publications

Involvement of the host DNA-repair enzyme TDP2 in formation of the covalently closed circular DNA persistence reservoir of hepatitis B viruses

Involvement of the host DNA-repair enzyme TDP2 in formation of the covalently closed circular DNA persistence reservoir of hepatitis B viruses

Improved antiviral efficacy using TALEN-mediated homology directed recombination to introduce artificial primary miRNAs into DNA of hepatitis B virus

Current and future directions for treating hepatitis B virus infection

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