When Hepatitis B Virus Meets Interferons

Chronic hepatitis B virus (HBV) infection imposes a severe burden on global public health. Currently, there are no curative therapies for millions of chronic HBV-infected patients (Lok et al., 2017). Interferon (IFN; including pegylated IFN) is an approved anti-HBV drug that not only exerts direct antiviral activity, but also augments immunity against HBV infection. Through a systematic review of the literature, here we summarize and present recent progress in research regarding the interactions between IFN and HBV as well as dissect the antiviral mechanisms of IFN. We focus on inhibition of HBV replication by IFN-stimulated genes (ISGs) as well as inhibition of IFN signaling by HBV and viral proteins. Finally, we briefly discuss current IFN-based HBV treatment strategies. This review may help to better understand the mechanisms involved in the therapeutic action of IFN as well as the crosstalk between IFN and HBV, and facilitate the development of both direct-acting and immunology-based new HBV drugs

New tricks for old NODs

The mammalian NOD-like receptor NLRX1 appears to have a role as a regulator of antiviral response pathways

Localization of the Major NF-κB-activating Site and the Sole TRAF3 Binding Site of LMP-1 Defines Two Distinct Signaling Motifs

The TRAF3 molecule interacts with the cytoplasmic carboxyl terminus (COOH terminus) of the Epstein-Barr virus-encoded oncogene LMP-1. NF-κB activation is a downstream signaling event of tumor necrosis factor receptor-associated factor (TRAF) molecules in other signaling systems (CD40 for example) and is an event caused by LMP-1 expression. One region capable of TRAF3 interaction in LMP-1 is the membrane-proximal 45 amino acids (188–242) of the COOH terminus. We show that this region contains the only site for binding of TRAF3 in the 200-amino acid COOH terminus of LMP-1. The site also binds TRAF2 and TRAF5, but not TRAF6. TRAF3 binds to critical residues localized between amino acids 196 and 212 (HHDDSLPHPQQATDDSG), including the PXQX(T/S) motif, that share limited identity to the CD40 receptor TRAF binding site (TAAPVQETL). Mutation of critical residues in the TRAF3 binding site of LMP-1 that prevents binding of TRAF2, TRAF3, and TRAF5 does not affect NF-κB-activating potential. Deletion mapping localized the major NF-κB activating region of LMP-1 to critical residues in the distal 4 amino acids of the COOH terminus (383–386). Therefore, TRAF3 binding and NF-κB activation occur through two separate motifs at opposite ends of the LMP-1 COOH-terminal sequence

Rapid Determination of Saponins in the Honey-Fried Processing of Rhizoma Cimicifugae by Near Infrared Diffuse Reflectance Spectroscopy.

ObjectiveA model of Near Infrared Diffuse Reflectance Spectroscopy (NIR-DRS) was established for the first time to determine the content of Shengmaxinside I in the honey-fried processing of Rhizoma Cimicifugae.MethodsShengmaxinside I content was determined by high-performance liquid chromatography (HPLC), and the data of the honey-fried processing of Rhizoma Cimicifugae samples from different batches of different origins by NIR-DRS were collected by TQ Analyst 8.0. Partial Least Squares (PLS) analysis was used to establish a near-infrared quantitative model.ResultsThe determination coefficient R² was 0.9878. The Cross-Validation Root Mean Square Error (RMSECV) was 0.0193%, validating the model with a validation set. The Root Mean Square Error of Prediction (RMSEP) was 0.1064%. The ratio of the standard deviation for the validation samples to the standard error of prediction (RPD) was 5.5130.ConclusionThis method is convenient and efficient, and the experimentally established model has good prediction ability, and can be used for the rapid determination of Shengmaxinside I content in the honey-fried processing of Rhizoma Cimicifugae

Identification of TRIM14 as a Type I IFN-Stimulated Gene Controlling Hepatitis B Virus Replication by Targeting HBx

Hepatitis B virus (HBV) remains a major cause of hepatic disease that threatens human health worldwide. Type I IFN (IFN-I) therapy is an important therapeutic option for HBV patients. The antiviral effect of IFN is mainly mediated via upregulation of the expressions of the downstream IFN-stimulated genes. However, the mechanisms by which IFN induces ISG production and inhibits HBV replication are yet to be clarified. TRIM14 was recently reported as a key molecule in the IFN-signaling pathway that regulates IFN production in response to viral infection. In this study, we sought to understand the mechanisms by which IFN restricts HBV replication. We confirmed that TRIM14 is an ISG in the hepatic cells, and that the pattern-recognition receptor ligands polyI:C and polydAdT induce TRIM14 dependent on IFN-I production. In addition, IFN-I-activated STAT1 (but not STAT3) directly bound to the TRIM14 promoter and mediated the induction of TRIM14. Interestingly, TRIM14 played an important role in IFN-I-mediated inhibition of HBV, and the TRIM14 SPRY domain interacted with the C-terminal of HBx, which might block the role of HBx in facilitating HBV replication by inhibiting the formation of the Smc-HBx–DDB1 complex. Thus, our study clearly demonstrates that TRIM14 is a STAT1-dependent ISG, and that the IFN-I–TRIM14–HBx axis shows an alternative way to understand the mechanism by which IFN-I inhibits virus replication

Attenuation of Cellular Inflammation Using Glucocorticoid-Functionalized Copolymers

This work has demonstrated the functionalization of an amphiphilic diblock copolymer, comprised of polyethylene oxide-polymethyl methacrylate (PEO-PMMA), as well as a triblock copolymer comprised of polymethyloxazoline-polydimethylsiloxane-polymethyloxazoline(PMOXA-PDMS-PM OXA) with the dexamethasone (Dex) glucocorticoid anti-inflammatory. Interfacial deposition of the copolymer and the Dex molecules and subsequent transfer of the hybrid materials to solid substrates were characterized to evaluate the potential of utilizing this composite material as a suppressor of cyto-inflammation to enhance implant biocompatibility. Given the extremely thin dimensions of the film (~4nm), this material would have negligible impact upon the size of the coated device to preclude biological stress. The composite films were interfaced with the RAW264.7 murine macrophages which served as a model cell line for the evaluation of nuclear factor-kappaB (NF-KB)-induced production of a host of inflammatory cytokines including interleukin-6, interleukin-12, tumor necrosis factor-alpha (TNFalpha), as well as the inducible nitric oxide synthase signaling factor which is known to be involved with stress-related processes such as neuronal damage. Lipopolysaccharide or LPS is a component of bacterial membranes that elicits cellular stress following application to RAW cell cultures. Following the induced stress response, significant reductions in the expression of genes associated with the aforementioned cytokines and signaling molecules indicated that macrophages in direct contact with the functionalized copolymer were able to collect Dex that was released from within the polymer network to attenuate cyto-inflammation mechanisms. This composite membrane represents a medically-relevant technology to promote chronic implant functionality and preclusion of bio-fouling

A TRAF3-NIK module differentially regulates DNA vs RNA pathways in innate immune signaling.

Detection of viral genomes by the innate immune system elicits an antiviral gene program mediated by type I interferons (IFNs). While viral RNA and DNA species induce IFN via separate pathways, the mechanisms by which these pathways are differentially modulated are unknown. Here we show that the positive regulator of IFN in the RNA pathway, TRAF3, has an inhibitory function in the DNA pathway. Loss of TRAF3 coincides with increased expression of the alternative NF-κB-inducing molecule, NIK, which interacts with the DNA pathway adaptor, STING, to enhance IFN induction. Cells lacking NIK display defective IFN activation in the DNA pathway due to impaired STING signaling, and NIK-deficient mice are more susceptible to DNA virus infection. Mechanistically, NIK operates independently from alternative NF-κB signaling components and instead requires autophosphorylation and oligomerization to activate STING. Thus a previously undescribed pathway for NIK exists in activating IFN in the DNA pathway

Regulating Innate and Adaptive Immunity for Controlling SIV Infection by 25-Hydroxycholesterol

Persistent inflammation and extensive immune activation have been associated with HIV-1/SIV pathogenesis. Previously, we reported that cholesterol-25-hydroxylase (CH25H) and its metabolite 25-hydroxycholesterol (25-HC) had a broad antiviral activity in inhibiting Zika, Ebola, and HIV-1 infection. However, the underlying immunological mechanism of CH25H and 25-HC in inhibiting viral infection remains poorly understood. We report here that 25-HC effectively regulates immune responses for controlling viral infection. CH25H expression was interferon-dependent and induced by SIV infection in monkey-derived macrophages and PBMC cells, and 25-HC inhibited SIV infection both in permissive cell lines and primary monkey lymphocytes. 25-HC also strongly inhibited bacterial lipopolysaccharide (LPS)-stimulated inflammation and restricted mitogen-stimulated proliferation in primary monkey lymphocytes. Strikingly, 25-HC promoted SIV-specific IFN-γ-producing cellular responses, but selectively suppressed proinflammatory CD4+ T lymphocytes secreting IL-2 and TNF-α cytokines in vaccinated mice. In addition, 25-HC had no significant immunosuppressive effects on cytotoxic CD8+ T lymphocytes or antibody-producing B lymphocytes. Collectively, 25-HC modulated both innate and adaptive immune responses toward inhibiting HIV/SIV infection. This study provides insights into improving vaccination and immunotherapy regimes against HIV-1 infection