Hepatitis B viruses: Reverse transcription a different way

Nassal, Michael

doi:10.1016/j.virusres.2007.12.024

Cited by 343 publications

(340 citation statements)

References 146 publications

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“…The typical hepadnavirus feature of restricting the bulk of reverse transcription to the inside of intact cytoplasmic nucleocapsids which then deliver the RC-DNA to the nuclear pore for release into the nucleoplasm (61) appears to be an appropriate strategy for avoiding such untimely encounters. If so, the most dangerous period would be the period immediately after P protein has bound to e, triggering both pgRNA encapsidation and replication initiation (5,6). The order of these events is unknown, but initiating assembly before reverse transcription would protect the replication-initiation complex from inappropriate TDP2 activity.…”

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.

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210

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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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.

Self Cite

210

193

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“…The viral genome is delivered to the host nucleus, where the positive sense strand is repaired, resulting in the conversion of RC to a covalently closed circular DNA (cccDNA) conformation, which is used as the viral transcription template. Various steps are seemingly required for RC to cccDNA conversion, however, these steps remain unclear [42].…”

Section: Viral Life Cyclementioning

confidence: 99%

“…Viral mRNAs, once transcribed, are transported to the host cytoplasm for translation and viral replication [42]. To produce viral progeny, pregenomic mRNA must be encapsidated by viral core protein, which self-assemble into the nucleocapsid once the viral polymerase binds a secondary stem-loop structure, epsilon, on the pregenomic mRNA [43][44][45][46].…”

Section: Viral Life Cyclementioning

confidence: 99%

Serological and molecular epidemiological outcomes after two decades of universal infant hepatitis B virus (HBV) vaccination in Nunavut, Canada

Huynh¹,

Minuk

Uhanova

et al. 2017

Vaccine

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“…6,7 The overlength pregenomic RNA (pgRNA) which act as a replication intermediate is reverse transcribed to form relaxed circular DNA (rcDNA), cccDNA as well as can produce truncated form of linear HBV dsDNA capable of integration. 8 As a consequence, persistence of cccDNA and integration of viral DNA in to host genome appeared as key factors responsible for relapse of HBV infection, failure of viral clearance after completion of antiviral therapy and development of HCC in CHB patients.…”

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confidence: 99%

Reduced Expression of DNA Damage Repair Genes High Mobility Group Box1 and Poly(ADP-ribose) Polymerase1 in Inactive Carriers of Hepatitis B Virus Infection-A Possible Stage of Viral Integration

Mukherjee

Shravanti

Jakkampudi

et al. 2013

Journal of Clinical and Experimental Hepatology

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Background: High mobility group box1 (HMGB1) and poly(ADP-ribose) polymerase1 (PARP1) proteins repair cellular DNA damage. Reduced expression of the corresponding genes can lead to an impaired DNA damage repair mechanism. Intracellular replication of hepatitis B virus (HBV) in such conditions can favor the integration of viral DNA into host genome leading to the development of hepatocellular carcinoma (HCC). Objective: This study was performed to assess the expression of HMGB1 and PARP1 mRNAs in conjunction with the estimation of HBV replication intermediate pregenomic RNA (PgRNA) in various phases of HBV infection. Materials: Eighty eight patients and 26 voluntary blood donors as controls were included in the study. Patients were grouped in to acute (AHB; n = 15), inactive carriers (IC; n = 36), cirrhosis (Cirr; n = 25) and hepatocellular carcinoma (HCC; n = 12). Serum HBV DNA was quantified by real time polymerase chain reaction (PCR) assay. Expression of HMGB1, PARP1 and PgRNA were evaluated using peripheral blood mononuclear cells (PBMCs) derived RNA by reverse transcription PCR (RT-PCR) and densitometry. Results: Significant reduction of HMGB1 and PARP1 gene expressions (P < 0.05) were observed in patients than controls with more explicit decline of PARP1 (P = 0.0002). Both genes were significantly downregulated (P < 0.001) in ICs than controls. In ICs, HMGB1 was significantly lowered than cirrhosis (P = 0.002) and HCC (P = 0.0006) while PARP1 declined significantly (P = 0.04) than HCC. Level of PgRNA was comparable in all the disease categories. Conclusion: In conclusion, our findings indicate impaired DNA damage repair mechanisms in HBV infected cells of ICs. This, along with low viral load but higher level of PgRNA in this group is suggestive of the diversion of HBV replication pathway that might facilitate viral DNA integration in to host genome. Intrusion of HBV PgRNA reverse transcription in early stage of infection might appear advantageous to thwart the development of HCC. ( J CLIN EXP HEPATOL 2013;3:89-95)

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Hepatitis B viruses: Reverse transcription a different way

Cited by 343 publications

References 146 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

Serological and molecular epidemiological outcomes after two decades of universal infant hepatitis B virus (HBV) vaccination in Nunavut, Canada

Reduced Expression of DNA Damage Repair Genes High Mobility Group Box1 and Poly(ADP-ribose) Polymerase1 in Inactive Carriers of Hepatitis B Virus Infection-A Possible Stage of Viral Integration

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