Activation of Pattern Recognition Receptor-Mediated Innate Immunity Inhibits the Replication of Hepatitis B Virus in Human Hepatocyte-Derived Cells

Guo, Haitao; Jiang, Dong; Ma, Dongling; Chang, Jinhong; Dougherty, Anne Marie; Cuconati, Andrea; Block, Timothy M.; Guo, Ju‐Tao

doi:10.1128/jvi.02008-08

Cited by 110 publications

(102 citation statements)

References 84 publications

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“…Recent work has demonstrated that an overexpression of the TLR adapters MyD88 or TRIF, or an overexpression of the RIG-I and MDA5 adapters, inhibits HBV replication in HepG2 and Huh7 cells, suggesting that HBV is sensitive to PRR-mediated IFN signaling and the cellular antiviral response. 29 Our observation that HBx is an inhibitor of virus-triggered induction of type I IFNs provides a mechanistic explanation for the observation that HBV fails to induce type I IFNs.…”

Section: Discussionmentioning

confidence: 74%

“…26 Recently, several groups demonstrated that forced induction of type I IFNs by the overexpression of TLR or RLR signaling components inhibits HBV replication in the following experimental systems: in vivo, 27 in mice non-parenchymal cells 28 and in HepG2 and Huh7 cells. 29 The Wu group also determined that Toll-like receptors mediate IRF3 and IFN-b activation and can be inhibited by a high level of HBV replication in HBV-Met cells. 30 These results suggest that HBV has evolved mechanisms to overcome the innate immune response of the host cell.…”

Section: Introductionmentioning

confidence: 99%

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Hepatitis B virus X protein suppresses virus-triggered IRF3 activation and IFN-β induction by disrupting the VISA-associated complex

Wang

Mao

et al. 2010

Cell Mol Immunol

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Viral RNAs produced during viral infection are recognized by the cytoplasmic RNA helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). A central adapter protein downstream of RIG-I and MDA5 is the mitochondrial membrane protein virus-induced signaling adaptor (VISA), which mediates the induction of type I interferons (IFNs) through the activation of transcription factors such as nuclear factor-kappaB (NF-kB) and IFN-regulatory factor-3 (IRF3). Here we found that hepatitis B virus (HBV)-encoded X protein (HBx) acts as an inhibitor of virus-triggered IRF3 activation and IFN-b induction. Reporter and plaque assays indicate that HBx inhibits signaling by components upstream but not downstream of VISA. Immunoprecipitation experiments indicate that HBx interacts with VISA and disrupts the association of VISA with its upstream and downstream components. These findings suggest that HBx acts as a suppressor of virus-triggered induction of type I IFNs, which explains the observation that HBV causes transient and chronic infection in hepatocytes but fails to activate the pattern recognition receptor-mediated IFN induction pathways.

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Section: Discussionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Hepatitis B virus X protein suppresses virus-triggered IRF3 activation and IFN-β induction by disrupting the VISA-associated complex

Wang

Mao

et al. 2010

Cell Mol Immunol

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“…To date, limited information is available regarding which HBV components stimulate relevant PAMP receptors. In general, activation of TLR-dependent pathways suppresses HBV replication both in vitro and in vivo [22].…”

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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“…Although the activation of the innate immune response has a key role in initiating the adaptive immune response, experimental results of HBV infection in both chimpanzees and woodchucks demonstrated non-or limited activation of innate immunity in acute HBV infection. 5,6 A number of recent studies [7][8][9][10] have investigated and suggested the involvement of innate cells, such as nature killer and nature killer T cells, in chronic HBV infection and suggested that these cells could play a role in liver damage during reactivation. Nevertheless, the role of innate immunity in viral clearance during HBV infection is still not clear.…”

Section: Introductionmentioning

confidence: 99%

Tumor necrosis factor-alpha blockage therapy impairs hepatitis B viral clearance and enhances T-cell exhaustion in a mouse model

Chyuan

Tsai²,

Tzeng

et al. 2015

Cell Mol Immunol

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Hepatitis B virus (HBV) reactivation and recurrence are common in patients undergoing immunosuppression therapy. Tumor necrosis factor (TNF) blockage therapy is effective for the treatment of many autoimmune inflammatory diseases. However, the role of TNF-a blockage therapy in the innate and adaptive immune responses against HBV is still not clear. A detailed analysis of HBV infection under TNF-a blockage therapy is essential for the prophylaxis and therapy for HBV reactivation and recurrence. In this study, HBV clearance and T-cell responses were analyzed in a HBV-transfected mouse model under anti-TNF blockage therapy. Our results demonstrated that under TNF-a blockage therapy, HBV viral clearance was impaired with persistent elevated HBV viral load in a dose-and temporal-dependent manner. The impairment of HBV clearance under anti-TNF-a blockage therapy occurred at early time points after HBV infection. In addition, TNF-a blockade maintained a higher serum HBV viral load and increased the number of intrahepatic programmed cell death (PD)-1 high CD127 low exhausted T cells. Furthermore, TNF-a blockade abolished Toll-like receptor 9 (TLR9) ligand-induced facilitation of HBV viral clearance. Taken together, TNF-a blockade impairs HBV clearance and enhances viral load, and these effects depend on early administration after HBV infection. Our results here demonstrate that early TNF-a blockade reduces viral clearance and persistently maintains elevated HBV viral load in a mouse model, suggesting that HBV may reactivate during therapy with TNF-a-blocking agents.

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Activation of Pattern Recognition Receptor-Mediated Innate Immunity Inhibits the Replication of Hepatitis B Virus in Human Hepatocyte-Derived Cells

Abstract: Recognition of virus infections by pattern recognition receptors (PRRs),

Cited by 110 publications

References 84 publications

Hepatitis B virus X protein suppresses virus-triggered IRF3 activation and IFN-β induction by disrupting the VISA-associated complex

Hepatitis B virus X protein suppresses virus-triggered IRF3 activation and IFN-β induction by disrupting the VISA-associated complex

Host–virus interactions in hepatitis B and hepatitis C infection

Tumor necrosis factor-alpha blockage therapy impairs hepatitis B viral clearance and enhances T-cell exhaustion in a mouse model

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