Equid Herpesvirus 1 Targets the Sensitization and Induction Steps To Inhibit the Type I Interferon Response in Equine Endothelial Cells
Fatai S. OladunniSanjay SarkarStephanie E. ReedyUdeni B. R. BalasuriyaDavid W. HorohovThomas M. Chambers
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Equid herpesvirus 1 (EHV-1) is a viral pathogen of horse populations worldwide spread by the respiratory route and is known for causing outbreaks of neurologic syndromes and abortion storms. Previously, we demonstrated that an EHV-1 strain of the neuropathogenic genotype, T953, downregulates the beta interferon (IFN-β) responseKeywords:
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PEDV refers to the alphacoronavirus that is found globally and has re-emerged recently, causing severe financial losses. In PEDV infection, the host activates various host restriction factors to maintain innate antiviral responses to suppress virus replication.
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The use of unique cell surface markers to target and eradicate HIV-infected cells has been a longstanding objective of HIV-1 cure research. This approach, however, overlooks the possibility that intracellular changes present within HIV-infected cells may serve as valuable therapeutic targets. For example, the identification of dysregulated antiviral signaling in cancer has led to the characterization of oncolytic viruses capable of preferentially killing cancer cells. Since impairment of cellular antiviral machinery has been proposed as a mechanism by which HIV-1 evades immune clearance, we hypothesized that HIV-infected macrophages (an important viral reservoir in vivo) would be preferentially killed by the interferon-sensitive oncolytic Maraba virus MG1. We first showed that HIV-infected monocyte-derived macrophages (MDM) were more susceptible to MG1 infection and killing than HIV-uninfected cells. As MG1 is highly sensitive to type I interferons (IFN-I), we then investigated whether we could identify IFN-I signaling differences between HIV-infected and uninfected MDM and found evidence of impaired IFN-α responsiveness within HIV-infected cells. Finally, to assess whether MG1 could target a relevant, primary cell reservoir of HIV-1, we investigated its effects in alveolar macrophages (AM) obtained from effectively treated individuals living with HIV-1. As observed with in vitro-infected MDM, we found that HIV-infected AM were preferentially eliminated by MG1. In summary, the oncolytic rhabdovirus MG1 appears to preferentially target and kill HIV-infected cells via impairment of antiviral signaling pathways and may therefore provide a novel approach to an HIV-1 cure.IMPORTANCE Human immunodeficiency virus type 1 (HIV-1) remains a treatable, but incurable, viral infection. The establishment of viral reservoirs containing latently infected cells remains the main obstacle in the search for a cure. Cure research has also focused on only one cellular target of HIV-1 (the CD4+ T cell) while largely overlooking others (such as macrophages) that contribute to HIV-1 persistence. In this study, we address these challenges by describing a potential strategy for the eradication of HIV-infected macrophages. Specifically, we show that an engineered rhabdovirus-initially developed as a cancer therapy-is capable of preferential infection and killing of HIV-infected macrophages, possibly via the same altered antiviral signaling seen in cancer cells. As this rhabdovirus is currently being explored in phase I/II clinical trials, there is potential for this approach to be readily adapted for use within the HIV-1 cure field.
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Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease characterized by the loss of tolerance to nuclear antigens, immune complex formation and inflammation in multiple organs. The disease is very heterogeneous, and most clinicians consider SLE as a group of diseases with similar features where the pathogenesis is driven by a combination of genetic and environmental factors. One of the most prominent features, shared by the majority of patients with SLE, is a continuous activation of the type I interferon (IFN) system, which manifests as increased serum levels of IFNα and/or an increased expression of type I IFN-induced genes, a so-called type I IFN signature. The mechanisms behind this IFN signature have partly been clarified during recent years, although the exact function of the IFN-regulated genes in the disease process is unclear. In this review, we will describe the type I IFN system and its regulation and summarize the numerous findings implicating an important ethiopathogenic role of a dysregulated type I IFN system in SLE. Furthermore, strategies to therapeutically target the type I IFN system that are currently evaluated preclinically and in clinical trials will be mentioned.
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Human interferon specifically inhibits the viral multiplication in a human cell line infected by a type D retrovirus, the Mason-Pfizer virus (MPV). This inhibition is less important than for type C viruses.
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Type I interferons, which make up the first cytokine family to be described and are the essential mediators of antivirus host defense, have emerged as central elements in the immunopathology of systemic autoimmune diseases, with systemic lupus erythematosus as the prototype. Lessons from investigation of interferon regulation following virus infection can be applied to lupus, with the conclusion that sustained production of type I interferon shifts nearly all components of the immune system toward pathologic functions that result in tissue damage and disease. We review recent data, mainly from studies of patients with systemic lupus erythematosus, that provide new insights into the mechanisms of induction and the immunologic consequences of chronic activation of the type I interferon pathway. Current concepts implicate endogenous nucleic acids, driving both cytosolic sensors and endosomal Toll-like receptors, in interferon pathway activation and suggest targets for development of novel therapeutics that may restore the immune system to health.
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Type I interferon (IFN) has been implicated in the pathogenesis of systemic lupus erythematosus (SLE) since the late 1970s when elevated serum levels were noted in patients with this autoimmune disease. More recently, the ability of SLE sera to induce IFN in normal peripheral blood mononuclear cells has been noted and led to the recognition of RNA/DNA-containing immune complexes as key components of this IFN-inducing factor. Interest in the field grew with the publication of several gene expression studies that documented activation of the type I IFN pathway in patients with SLE. This activation was associated with disease activity and severity. The important implications of these advances for the management of patients with SLE are twofold. First, IFN may be a useful biomarker of disease subtype and activity and, second, IFN is a rational target for therapeutic intervention. Cautious blockade of this pathway might eliminate an important contributor to autoimmunity.
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The type I interferon (IFN) system is our main defense against viral infections and consists of a large number of sensors of nucleic acid that can trigger the production of more than 15 different proteins with antiviral and immunostimulatory capacity. There are several observations suggesting an important role for this system in the etiopathogenesis of systemic lupus erythematosus (SLE) and other autoimmune diseases. Among these are the development of autoimmune diseases during IFN-α treatment, a prominent increase in the expression of type I IFN regulated genes (an IFN signature) in a number of rheumatic diseases, the existence of endogenous IFN inducers in SLE patients and a genetic association between autoimmune diseases and gene variants within the type I IFN signalling pathway. Collectively, these observations suggests that inhibition of the type I IFN system could be beneficial in SLE and possible also other autoimmune diseases. Many different therapeutic targets exist and several studies are in progress aiming to block or down-regulate the activated type I IFN system. A number of studies with monoclonal anti-IFN-α antibodies in SLE patients have been reported, and a small study investigating vaccination with an interferon-α-kinoid against IFN-α has been published. Trials targeting the type I IFN receptor are under way, and other possibilities include elimination of the endogenous IFN inducers and inhibition of key molecules in the type I IFN signalling pathway. Results so far show that it is possible to partially suppress the IFN signature, improve several biomarkers and ameliorate clinical manifestations by some of these new treatment strategies.
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ABSTRACT Infection of cells with flaviviruses in vitro is reduced by pretreatment with small amounts of type I interferon (IFN-α/β). Similarly, pretreatment of animals with IFN and experiments using mice defective in IFN signaling have indicated a role for IFN in controlling flavivirus disease in vivo. These data, along with findings that flavivirus-infected cells block IFN signaling, suggest that flavivirus infection can trigger an IFN response. To investigate IFN gene induction by the very first cells infected during in vivo infection with the flavivirus West Nile virus (WNV), we infected mice with high-titer preparations of WNV virus-like particles (VLPs), which initiate viral genome replication in cells but fail to spread. These studies demonstrated a brisk production of IFN in vivo, with peak levels of over 1,000 units/ml detected in sera between 8 and 24 h after inoculation by either the intraperitoneal or footpad route. The IFN response was dependent on genome replication, and WNV genomes and WNV antigen-positive cells were readily detected in the popliteal lymph nodes (pLN) of VLP-inoculated mice. High levels of IFN mRNA transcripts and functional IFN were also produced in VLP-inoculated IFN regulatory factor 3 null (IRF3 −/− ) mice, indicating that IFN production was independent of the IRF3 pathways to IFN gene transcription, consistent with the IFN type produced (predominantly α).
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