Hepatitis B Virus Limits Response of Human Hepatocytes to Interferon-α in Chimeric Mice

Lütgehetmann, Marc; Bornscheuer, T.; Volz, Tassilo; Allweiss, Lena; Bockmann, Jan-Hendrik; Pollok, Joerg M.; Lohse, Ansgar W.; Petersen, J.; Dandri, Maura

doi:10.1053/j.gastro.2011.02.057

Cited by 138 publications

(121 citation statements)

References 38 publications

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“…Inhibition of the key IFN-a signal transducer Stat1 by HBV has been suggested to antagonize the IFN response (35,36). In this study, we found that miR-146a, which targets Stat1, is significantly upregulated in the T cells of patients with CHB, which could shed light on the mechanism of the limited effectiveness of therapeutic IFN-a in CHB.…”

Section: Discussionmentioning

confidence: 56%

MicroRNA-146a Feedback Suppresses T Cell Immune Function by Targeting Stat1 in Patients with Chronic Hepatitis B

Wang

Zhang

et al. 2013

The Journal of Immunology

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More than 350 million people are chronically infected with hepatitis B virus, and dysfunctional T cell responses contribute to persistent viral infection and immunopathogenesis in chronic hepatitis B (CHB). However, the underlying mechanisms of T cell hyporesponsiveness remain largely undefined. Given the important role of microRNA-146a (miR-146a) in diverse aspects of lymphocyte function, we investigated the potential role and mechanism of miR-146a in regulating T cell immune responses in CHB. We found that miR-146a expression in T cells is significantly upregulated in CHB compared with healthy controls, and miR-146a levels were correlated with serum alanine aminotransaminase levels. Both inflammatory cytokines and viral factors led to miR-146a upregulation in T cells. Stat1 was identified as a miR-146a target that is involved in antiviral cytokine production and the cytotoxicity of CD4+ and CD8+ T cells. In vitro blockage of miR-146a in T cells in CHB greatly enhanced virus-specific T cell activity. Therefore, our work demonstrates that miR-146a upregulation in CHB causes impaired T cell function, which may contribute to immune defects and immunopathogenesis during chronic viral infection.

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Section: Discussionmentioning

confidence: 56%

MicroRNA-146a Feedback Suppresses T Cell Immune Function by Targeting Stat1 in Patients with Chronic Hepatitis B

Wang

Zhang

et al. 2013

The Journal of Immunology

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“…Although we do not have formal evidence, these results also suggest that, in response to IFN-α, there is a dynamic change in the quality of the complexes bound to the HBV ISRE with loss of phosphorylated STAT2 and STAT1 and a decrease of unphosphorylated STAT proteins. In this respect, it is noteworthy that chronic HBV infection of human hepatocytes transplanted in uPA/SCID mice impairs the induction of IFN-α target genes by inhibiting nuclear translocation of STAT1 (16). The presence of STAT1 and STAT2 complexes on the cccDNA before IFN-α treatment apparently defies the classical paradigm of the STATs as latent transcription factors in the cytoplasm, entering the nucleus to induce gene expression only in response to cytokine stimulation to bind DNA and activate their transcriptional program, but it is not unprecedented.…”

Section: Ifn-α Inhibits Cccdna Transcription and Hbv Replication In Hmentioning

confidence: 99%

“…To this aim, we made use first of a plasmid-free HBV transfection cell-based replication assay relying on the generation of transcriptionally active nuclear cccDNA to replicate HBV (3,14). Second, SCID/beige mice transgenic for the urokinase plasminogen activator (uPA) under control of the albumin promoter were used to repopulate mouse livers with human hepatocytes derived from a single liver donor (15,16). This model minimizes the impact of host variation factors and allows the investigation of in vivo interactions occurring between HBV and human hepatocytes, the natural target cell of infection and replication.…”

Section: Introductionmentioning

confidence: 99%

IFN-α inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome

Belloni¹,

Allweiss²,

Guerrieri³

et al. 2012

J. Clin. Invest.

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422

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HBV infection remains a leading cause of death worldwide. IFN-α inhibits viral replication in vitro and IntroductionHepatitis B Virus (HBV) infection remains a major health problem worldwide despite the availability of a highly effective preventive vaccine. HBV is a noncytopathic hepatotropic DNA virus that belongs to the family Hepadnaviridae, whose members share a distinctive strategy for replication. HBV replication occurs in the cytoplasm within viral capsids (core particles), where a genomesized RNA replicative intermediate, termed the pregenome (pgRNA), is converted by the virally encoded RNA-dependent and DNA-dependent reverse transcriptase/polymerase into a specific open circular (OC) duplex DNA (1). Transcription in the nucleus of the pgRNA from the covalently closed circular DNA (cccDNA) is the critical step for genome amplification and ultimately determines the rate of HBV replication (2). The cccDNA, which also serves as the template for the transcription of all viral messenger RNAs, is organized into a minichromosome in the nuclei of infected hepatocytes by histone and nonhistone proteins, and its function is regulated, similarly to cellular chromatin, by the activity of nuclear transcription factors, transcriptional coactivators and corepressors, and chromatin-modifying enzymes (2-4).Current antiviral therapies involve the use of nucleoside analogs and pegylated IFN-α (5). IFN-α, a type I IFN, engages the IFN-α/β receptor complex to activate the intracellular Jak/Stat signaling pathway, which modulates the transcription of a diverse set of target genes, referred to as IFN-stimulated genes (ISGs) (6). ISG

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“…In the shared downstream pathway of TLR and RIG-I, HBV polymerase is responsible for IRF3 inhibition at the levels of kinases TBK1/IKKe [27] and has been reported to inhibit STING-stimulated IRF3 activation and IFN-b induction [28]. HBV infection causes the inhibition of the nuclear translocation of STAT1 [29], the blockade of the TLR9-MyD88-IRAK4 axis in pDCs, or the impediment of TLR3/RIG-I signaling in hepatocytes [30]. The role of innate immunity in HBV control might be impaired for these mechanisms.…”

Section: Pattern Recognition Receptors In Hbv Infectionmentioning

confidence: 99%

Host–virus interactions in hepatitis B and hepatitis C infection

Yoshio

Kanto

2016

J Gastroenterol

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Hepatitis B virus (HBV) and hepatitis C virus (HCV) are among the most endemic pathogens worldwide, with more than 500 million people globally currently infected with these viruses. These pathogens can cause acute and chronic hepatitis that progress to liver cirrhosis or hepatocellular carcinoma. Both viruses utilize multifaceted strategies to evade the host surveillance system and fall below the immunological radar. HBV has developed specific strategies to evade recognition by the innate immune system and is acknowledged to be a stealth virus. However, extensive research has revealed that HBV is recognized by dendritic cells (DCs) and natural killer (NK) cells. Indoleamine-2, 3-dioxygenase is an enforcer of sequential immune reactions in acute hepatitis B, and this molecule has been shown to be induced by the interaction of HBV-infected hepatocytes, DCs, and NK cells. The interleukin-28B genotype has been reported to influence HCV eradication either therapeutically or spontaneously, but the biological function of its gene product, a type-III interferon (IFN-k3), remains to be elucidated. Human BDCA3 ? DCs have also been shown to be a potent producer of IFN-k3 in HCV infection, suggesting the possibility that BDCA3 ? DCs could play a key role in developing therapeutic HCV vaccine. Here we review the current state of research on immune responses against HBV and HCV infection, with a specific focus on innate immunity. A comprehensive study based on clinical samples is urgently needed to improve our understanding of the immune mechanisms associated with viral control and thus to develop novel immune modulatory therapies to cure chronic HBV and HCV infection.

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Hepatitis B Virus Limits Response of Human Hepatocytes to Interferon-α in Chimeric Mice

Cited by 138 publications

References 38 publications

MicroRNA-146a Feedback Suppresses T Cell Immune Function by Targeting Stat1 in Patients with Chronic Hepatitis B

MicroRNA-146a Feedback Suppresses T Cell Immune Function by Targeting Stat1 in Patients with Chronic Hepatitis B

IFN-α inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome

Host–virus interactions in hepatitis B and hepatitis C infection

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