Innate immunity and HBV persistence

Chiale, Carolina; Marchese, Anthony M.; Robek, Michael D.

doi:10.1016/j.coviro.2021.04.003

Cited by 15 publications

(14 citation statements)

References 83 publications

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“…Induction of virus-specific adaptive immunity, including T- and B-cell responses, is considered the hallmark for the resolution of either HBV or WHV infection ( 48 , 49 ). The role of innate immune cells, including natural killer (NK) cells, dendritic cells (DCs), and macrophages, and the involvement of PRRs in the resolution of HBV infection is only just emerging ( 50 , 51 ). Recent studies demonstrated the in vitro recognition of HBV nucleic acids by PRRs, such as cytosolic RIG-I sensing the 5’ ε structure of HBV pgRNA ( 52 ) and nucleus resident IFI16 sensing HBV cccDNA ( 36 ), thereby promoting the suppression of these key viral molecules.…”

Section: Discussionmentioning

confidence: 99%

Agonistic Activation of Cytosolic DNA Sensing Receptors in Woodchuck Hepatocyte Cultures and Liver for Inducing Antiviral Effects

Suresh

Huang

et al. 2021

Front. Immunol.

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Immune modulation for the treatment of chronic hepatitis B (CHB) has gained more traction in recent years, with an increasing number of compounds designed for targeting different host pattern recognition receptors (PRRs). These agonistic molecules activate the receptor signaling pathway and trigger an innate immune response that will eventually shape the adaptive immunity for control of chronic infection with hepatitis B virus (HBV). While definitive recognition of HBV nucleic acids by PRRs during viral infection still needs to be elucidated, several viral RNA sensing receptors, including toll-like receptors 7/8/9 and retinoic acid inducible gene-I-like receptors, are explored preclinically and clinically as possible anti-HBV targets. The antiviral potential of viral DNA sensing receptors is less investigated. In the present study, treatment of primary woodchuck hepatocytes generated from animals with CHB with HSV-60 or poly(dA:dT) agonists resulted in increased expression of interferon-gamma inducible protein 16 (IFI16) or Z-DNA-binding protein 1 (ZBP1/DAI) and absent in melanoma 2 (AIM2) receptors and their respective adaptor molecules and effector cytokines. Cytosolic DNA sensing receptor pathway activation correlated with a decline in woodchuck hepatitis virus (WHV) replication and secretion in these cells. Combination treatment with HSV-60 and poly(dA:dT) achieved a superior antiviral effect over monotreatment with either agonist that was associated with an increased expression of effector cytokines. The antiviral effect, however, could not be enhanced further by providing additional type-I interferons (IFNs) exogenously, indicating a saturated level of effector cytokines produced by these receptors following agonism. In WHV-uninfected woodchucks, a single poly(dA:dT) dose administered via liver-targeted delivery was well-tolerated and induced the intrahepatic expression of ZBP1/DAI and AIM2 receptors and their effector cytokines, IFN-β and interleukins 1β and 18. Receptor agonism also resulted in increased IFN-γ secretion of peripheral blood cells. Altogether, the effect on WHV replication and secretion following in vitro activation of IFI16, ZBP1/DAI, and AIM2 receptor pathways suggested an antiviral benefit of targeting more than one cytosolic DNA receptor. In addition, the in vivo activation of ZBP1/DAI and AIM2 receptor pathways in liver indicated the feasibility of the agonist delivery approach for future evaluation of therapeutic efficacy against HBV in woodchucks with CHB.

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Section: Discussionmentioning

confidence: 99%

Agonistic Activation of Cytosolic DNA Sensing Receptors in Woodchuck Hepatocyte Cultures and Liver for Inducing Antiviral Effects

Suresh

Huang

et al. 2021

Front. Immunol.

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“…Current evidence shows that RIG-I can recognize HBV pregenomic RNA and suppress HBV cccDNA, thereby activating the innate immune response to inhibit its replication (80)(81)(82). Similar to TLR, drugs activating RLR signaling also underwent a phase II trial to investigate the therapeutic effects of PLR agonists on HBV inhibition in clinical settings (13). It was found that the virus could escape immune reactions by regulating RLR signaling (13).…”

Section: Role Of Hbx In Rlr-mediated Signaling Pathwaysmentioning

confidence: 99%

“…Similar to TLR, drugs activating RLR signaling also underwent a phase II trial to investigate the therapeutic effects of PLR agonists on HBV inhibition in clinical settings ( 13 ). It was found that the virus could escape immune reactions by regulating RLR signaling ( 13 ). For example, no significant increase in RIG-I and MDA5 levels was found in the liver tissues of patients with CHB ( 83 ).…”

Section: Role Of Hbx In Rlr-mediated Signaling Pathwaysmentioning

confidence: 99%

“…Additionally, these PRRs can stimulate the production of inflammatory cytokines induced by the nuclear factor kB (NF-kB) pathway to resist the virus (11,12). However, accumulating evidence suggests that to maintain persistent infection, the virus has evolved a variety of strategies to overcome the host antiviral responses mediated by PRR components, such as TLRs, cytosolic DNA sensors, RLRs, and NLRs, as well as their downstream pathways, including the JAK-STAT and NF-kB pathways, to facilitate viral replication and liver pathogenesis (13)(14)(15)(16). Moreover, the exact mechanisms by which this virus evades the immune response mediated by PRRs to facilitate its persistent infection and development of different diseases remain elusive.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Pattern-Recognition Receptor Signaling by HBX During Hepatitis B Virus Infection

et al. 2022

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As a small DNA virus, hepatitis B virus (HBV) plays a pivotal role in the development of various liver diseases, including hepatitis, cirrhosis, and liver cancer. Among the molecules encoded by this virus, the HBV X protein (HBX) is a viral transactivator that plays a vital role in HBV replication and virus-associated diseases. Accumulating evidence so far indicates that pattern recognition receptors (PRRs) are at the front-line of the host defense responses to restrict the virus by inducing the expression of interferons and various inflammatory factors. However, depending on HBX, the virus can control PRR signaling by modulating the expression and activity of essential molecules involved in the toll-like receptor (TLR), retinoic acid inducible gene I (RIG-I)-like receptor (RLR), and NOD-like receptor (NLR) signaling pathways, to not only facilitate HBV replication, but also promote the development of viral diseases. In this review, we provide an overview of the mechanisms that are linked to the regulation of PRR signaling mediated by HBX to inhibit innate immunity, regulation of viral propagation, virus-induced inflammation, and hepatocarcinogenesis. Given the importance of PRRs in the control of HBV replication, we propose that a comprehensive understanding of the modulation of cellular factors involved in PRR signaling induced by the viral protein may open new avenues for the treatment of HBV infection.

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“…However, in the late stages of infection, HBV dysregulates the host immune function as a contradictory strategy to escape from viral recognition which leads to the establishment of viral persistence [81].…”

Section: Hbv and Innate Immune Systemmentioning

confidence: 99%

Interaction between the Hepatitis B Virus and Cellular FLIP Variants in Viral Replication and the Innate Immune System

Lee

Park

Dezhbord

et al. 2022

Viruses

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During viral evolution and adaptation, many viruses have utilized host cellular factors and machinery as their partners. HBx, as a multifunctional viral protein encoded by the hepatitis B virus (HBV), promotes HBV replication and greatly contributes to the development of HBV-associated hepatocellular carcinoma (HCC). HBx interacts with several host factors in order to regulate HBV replication and evolve carcinogenesis. The cellular FADD-like IL-1β-converting enzyme (FLICE)-like inhibitory protein (c-FLIP) is a major factor that functions in a variety of cellular pathways and specifically in apoptosis. It has been shown that the interaction between HBx and c-FLIP determines HBV fate. In this review, we provide a comprehensive and detailed overview of the interplay between c-FLIP and HBV in various environmental circumstances. We describe strategies adapted by HBV to establish its chronic infection. We also summarize the conventional roles of c-FLIP and highlight the functional outcome of the interaction between c-FLIP and HBV or other viruses in viral replication and the innate immune system.

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Innate immunity and HBV persistence

Cited by 15 publications

References 83 publications

Agonistic Activation of Cytosolic DNA Sensing Receptors in Woodchuck Hepatocyte Cultures and Liver for Inducing Antiviral Effects

Agonistic Activation of Cytosolic DNA Sensing Receptors in Woodchuck Hepatocyte Cultures and Liver for Inducing Antiviral Effects

Regulation of Pattern-Recognition Receptor Signaling by HBX During Hepatitis B Virus Infection

Interaction between the Hepatitis B Virus and Cellular FLIP Variants in Viral Replication and the Innate Immune System

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