Have the Starting Lineup of Five for Hepatitis B Virus Covalently Closed Circular DNA Synthesis Been Identified?

Zhao, Qiong; Guo, Ju‐Tao

doi:10.1002/hep.31408

Cited by 11 publications

(5 citation statements)

References 8 publications

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“…Interestingly, it was reported recently that the phosphorylation status of residues S44 and S49 at Cp assembly domain affects the production and conversion of minus-strand covalently closed rcDNA, an intermediate of cccDNA synthesis Zhao and Guo, 2020), to cccDNA, strongly suggesting a possible role of Cp in cccDNA synthesis in the nucleus (Luo et al, 2020). In addition, a recent proteomic analysis identified 60 Cp-interacting proteins in the nuclei of human hepatocytes.…”

Section: Core Protein: Possible Roles In Cccdna Function and Virus-host Cell Interactionmentioning

confidence: 99%

Targeting the multifunctional HBV core protein as a potential cure for chronic hepatitis B

Viswanathan

Mani²,

et al. 2020

Antiviral Research

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The core (capsid) protein of hepatitis B virus (HBV) is the building block of nucleocapsids where viral DNA reverse transcriptional replication takes place and mediates virus-host cell interaction important for the persistence of HBV infection. The pleiotropic role of core protein (Cp) in HBV replication makes it an attractive target for antiviral therapies of chronic hepatitis B, a disease that affects more than 257 million people worldwide without a cure. Recent clinical studies indicate that core protein allosteric modulators (CpAMs) have a great promise as a key component of hepatitis B curative therapies. Particularly, it has been demonstrated that modulation of Cp dimerdimer interactions by several chemical series of CpAMs not only inhibit nucleocapsid assembly and viral DNA replication, but also induce the disassembly of double-stranded DNA-containing nucleocapsids to prevent the synthesis of cccDNA. Moreover, the different chemotypes of CpAMs modulate Cp assembly by interaction with distinct amino acid residues at the HAP pocket between Cp dimer-dimer interfaces, which results in the assembly of Cp dimers into either non-capsid Cp polymers (type I CpAMs) or empty capsids with distinct physical property (type II CpAMs). The different CpAMs also differentially modulate Cp metabolism and subcellular distribution, which may impact cccDNA metabolism and host antiviral immune responses, the critical factors for the cure of chronic HBV infection. This review article highlights the recent research progress on the structure and function of core protein in HBV replication cycle, the mode of action of CpAMs, as well as the current status and perspectives on the discovery and development of core proteintargeting antivirals. This article forms part of a symposium in Antiviral Research on "Wideranging immune and direct-acting antiviral approaches to curing HBV and HDV infections."

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Section: Core Protein: Possible Roles In Cccdna Function and Virus-host Cell Interactionmentioning

confidence: 99%

Targeting the multifunctional HBV core protein as a potential cure for chronic hepatitis B

Viswanathan

Mani²,

et al. 2020

Antiviral Research

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“…Indeed, this step relies on the cellular DNA repair machinery, and cell culture conditions may largely influence this process. Cell-based genetic approaches, using siRNA or Crispr/Cas9, are difficult to implement because of the importance of the DNA repair proteins in cell survival and in vitro biochemical systems have been used to mimic rcDNA to cccDNA [ 26 , 27 ]. We propose to use these different culture conditions as a complementary approach to confirm the involvement of cellular factors in this process [ 26 ] and possibly discover additional ones.…”

Section: Discussionmentioning

confidence: 99%

Fast Differentiation of HepaRG Cells Allowing Hepatitis B and Delta Virus Infections

Michelet

Salvetti

Durantel

2020

Cells

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HepaRG cells are liver bipotent progenitors acquiring hepatocytes features when differentiated in the presence of dimethylsulfoxide (DMSO). Differentiated HepaRG (dHepaRG) are considered the best surrogate model to primary human hepatocytes (PHH) and are susceptible to several hepatotropic viruses, including Hepatitis B Virus (HBV) and Hepatitis Delta Virus (HDV) infection. Despite these advantages, HepaRG cells are not widely used for the study of these two viruses because of their long differentiation process and their rather low and variable infection rates. Here, we tested the use of a cocktail of five chemicals (5C) combined or not with DMSO to accelerate the cells’ differentiation process. We found that NTCP-mediated HDV entry and replication are similar in HepaRG cells cultivated for only 1 week with 5C and DMSO or differentiated with the regular 4-week protocol. However, even though the NTCP-mediated HBV entry process seemed similar, cccDNA and subsequent HBV replication markers were lower in HepaRG cells cultivated for 1 week with 5C and DMSO compared to the regular differentiation protocol. In conclusion, we set up a new procedure allowing fast differentiation and efficient HDV-infection of HepaRG cells and identified differential culture conditions that may allow to decipher the mechanism behind the establishment of the HBV minichromosome.

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“…The ability to eliminate or inactivate HBV cccDNA has been considered as the “holy grail” of HBV treatments [ 93 ] because achieving a “functional cure” for chronic HBV infections requires the permanent inactivation or degradation of the cccDNA [ 131 ]. Steps toward disrupting cccDNA have been enabled by understanding the roles of host enzymes such as TDP2, FEN1, and Pol-K in cccDNA formation.…”

Section: Novel Therapeutic Strategiesmentioning

confidence: 99%

Recent Advances in Hepatitis B Treatment

et al. 2021

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Hepatitis B virus infection affects over 250 million chronic carriers, causing more than 800,000 deaths annually, although a safe and effective vaccine is available. Currently used antiviral agents, pegylated interferon and nucleos(t)ide analogues, have major drawbacks and fail to completely eradicate the virus from infected cells. Thus, achieving a “functional cure” of the infection remains a real challenge. Recent findings concerning the viral replication cycle have led to development of novel therapeutic approaches including viral entry inhibitors, epigenetic control of cccDNA, immune modulators, RNA interference techniques, ribonuclease H inhibitors, and capsid assembly modulators. Promising preclinical results have been obtained, and the leading molecules under development have entered clinical evaluation. This review summarizes the key steps of the HBV life cycle, examines the currently approved anti-HBV drugs, and analyzes novel HBV treatment regimens.

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Have the Starting Lineup of Five for Hepatitis B Virus Covalently Closed Circular DNA Synthesis Been Identified?

Cited by 11 publications

References 8 publications

Targeting the multifunctional HBV core protein as a potential cure for chronic hepatitis B

Targeting the multifunctional HBV core protein as a potential cure for chronic hepatitis B

Fast Differentiation of HepaRG Cells Allowing Hepatitis B and Delta Virus Infections

Recent Advances in Hepatitis B Treatment

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