Cytidine deamination and cccDNA degradation: A new approach for curing HBV?

Ding, Siyuan; Robek, Michael D.

doi:10.1002/hep.27386

Cited by 9 publications

(7 citation statements)

References 19 publications

(25 reference statements)

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“…Although the mechanism by which HBV fails to induce a sufficient immune response in chronic carriers remains to be elucidated, it is conceivable that intrahepatic activation of the TLR response or the STING pathway in liver sinusoidal endothelial cells, Kupffer cells, and/or dendritic cells may promote the priming and activation of an anti-HBV adaptive immune response, as well as induce an antiviral cytokine response (44,45). These effects not only suppress HBV replication but also reduce the viral antigen load through the suppression of cccDNA transcription (46) or even promotion of cccDNA decay (47,48), which may attenuate the T cell exhaustion and favor the restoration of the HBV-specific T cell response.…”

Section: Discussionmentioning

confidence: 99%

STING Agonists Induce an Innate Antiviral Immune Response against Hepatitis B Virus

Guo

Han

Zhao

et al. 2015

Antimicrob Agents Chemother

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e Chronicity of hepatitis B virus (HBV) infection is due to the failure of a host to mount a sufficient immune response to clear the virus. The aim of this study was to identify small-molecular agonists of the pattern recognition receptor (PRR)-mediated innate immune response to control HBV infection. To achieve this goal, a coupled mouse macrophage and hepatocyte culture system mimicking the intrahepatic environment was established and used to screen small-molecular compounds that activate macrophages to produce cytokines, which in turn suppress HBV replication in a hepatocyte-derived stable cell line supporting HBV replication in a tetracycline-inducible manner. An agonist of the mouse stimulator of interferon ( Hepatitis B virus (HBV) is a noncytopathic hepadnavirus that chronically infects more than 350 million people worldwide. The outcomes and pathogenesis of HBV infections are largely determined by the nature and magnitude of the host antiviral immune response (1), which is generally related to the person's age at the time of infection. While over 95% of adult-acquired infections are spontaneously cleared within 6 months by a vigorous and polyclonal HBV-specific T cell response, more than 90% of exposed neonates and approximately 30% of children 1 to 5 years old develop a chronic infection (2, 3), which is associated with a weaker and often barely detectable virus-specific T cell response.Sustained suppression of viral replication by long-term nucleos(t)ide analogue therapy or through a finite duration of pegylated alpha interferon (IFN-␣) therapy has been associated with improvement of liver diseases, prevention of liver decompensation, and reduction of hepatocellular carcinoma morbidity and mortality (4, 5). However, a "functional cure," characterized by normalization of liver function, HBV surface antigen (HBsAg) seroconversion, and durable immune control of HBV replication, is rarely achieved with the current therapies (6, 7). Hence, the restoration of host innate and HBV-specific adaptive immune responses is essential for a functional cure of chronic HBV infection (8).Although hepatocytes are the primary host cells of HBV, hepatic nonparenchymal cells (NPCs) have been shown to play a critical role in the priming of effective HBV-specific antiviral immunity (9, 10). For instance, it was demonstrated recently that activation of hepatic macrophages induces the expression of a distinct profile of cytokines/chemokines that regulate the priming of a successful immune response against HBV in the livers of mice (10). It is therefore conceivable that pharmacological activation of Kupffer cells and/or intrahepatic dendritic cells with agonists of Toll-like receptors (TLRs) or other pattern recognition receptors (PRRs) may facilitate the intrahepatic priming of an anti-HBV immune response. In support of this hypothesis, it has been demonstrated recently in woodchucks and chimpanzees that administration of TLR7 agonists not only induced an innate cytokine response that suppresses HBV replication but also shaped...

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Section: Discussionmentioning

confidence: 99%

STING Agonists Induce an Innate Antiviral Immune Response against Hepatitis B Virus

Guo

Han

Zhao

et al. 2015

Antimicrob Agents Chemother

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“…To eradicate HBV, new therapies for chronic infections need to be devised. With the identification of the cell receptor for HBV 29 and new approaches to targeting cccDNA, the mini-chromosome of HBV, 30 such drugs will soon become a reality.…”

Section: Hepatocellular Carcinoma (Hcc) Risk Factors and Preventionmentioning

confidence: 99%

Global Epidemiology of Hepatocellular Carcinoma

McGlynn

Petrick

London

2015

Clinics in Liver Disease

683

303

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“…The NAs targeting the HBV polymerase (or termed reverse transcriptase) can substantially inhibit HBV replication, but it fails to eliminate the pre-existing HBV persistence template-the covalently closed circular DNA (cccDNA) [4]. Apart from the ISG-associated inhibitory activity against HBV replication [5], it's report that the IFNα at high concentration can degrade cccDNA in a noncytopathic manner [6,7]. Thus, the IFNα therapy can occasionally result in functional cure of CHB in some patients, but it suffers severe systemic side-effects as well as poor response rate [4].…”

Section: Introductionmentioning

confidence: 99%

Minicircle DNA vector expressing interferon-lambda-3 inhibits hepatitis B virus replication and expression in hepatocyte-derived cell line

Guo

Chen

Cai

et al. 2020

BMC Mol and Cell Biol

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Background: Interferon-alpha (IFNα) is a first-line treatment option for chronic hepatitis B virus (HBV) infection, but the severe systemic side-effects limited its clinical application. Interferon-lambda (IFNλ) with comparable antiviral activity and less toxic side-effects is thought to be a good alternative interferon to IFNα. Additionally, the gene vector mediated sustainably expression of therapeutic product in the target cells/tissue may overcome the shortcomings resulted from the short half-life of IFNs. Results: We constructed a liver-specific IFNλ3-expressing minicircle (MC) vector under the control of a hepatocytespecific ApoE promoter (MC.IFNλ3) and investigated its anti-HBV activity in a HBV-expressing hepatocyte-derived cell model (HepG2.2.15). As expected, the MC.IFNλ3 vector capable of expressing IFNλ3 in the recipient hepatocytes has demonstrated robust anti-HBV activity, in terms of suppressing viral antigen expression and viral DNA replication, via activation the interferon-stimulated gene (ISG) expression in HepG2.2.15 cells. Conclusions: Given the MC vector can be easily delivered into liver, the liver-targeted IFN gene-transfer (MC.IFNλ3), instead of systemic administrating IFN repeatedly, provides a promising concept for the treatment of chronic HBV infection.

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Cytidine deamination and cccDNA degradation: A new approach for curing HBV?

Cited by 9 publications

References 19 publications

STING Agonists Induce an Innate Antiviral Immune Response against Hepatitis B Virus

STING Agonists Induce an Innate Antiviral Immune Response against Hepatitis B Virus

Global Epidemiology of Hepatocellular Carcinoma

Minicircle DNA vector expressing interferon-lambda-3 inhibits hepatitis B virus replication and expression in hepatocyte-derived cell line

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