Virus-induced type I IFN stimulates generation of immunoproteasomes at the site of infection

Immunology Section and Liver Diseases Branch, NIDDK, NIH, Department of Health and Human Services, Bethesda, Maryland 20892, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 12/2006; 116(11):3006-14. DOI: 10.1172/JCI29832
Source: PubMed


IFN-gamma is known as the initial and primary inducer of immunoproteasomes during viral infections. We now report that type I IFN induced the transcription and translation of immunoproteasome subunits, their incorporation into the proteasome complex, and the generation of an immunoproteasome-dependent CD8 T cell epitope in vitro and provide in vivo evidence that this mechanism occurs prior to IFN-gamma responses at the site of viral infection. Type I IFN-mediated generation of immunoproteasomes was initiated by either poly(I:C) or HCV RNA in human hepatoma cells and was inhibited by neutralization of type I IFN. In serial liver biopsies of chimpanzees with acute HCV infection, increases in immunoproteasome subunit mRNA preceded intrahepatic IFN-gamma responses by several weeks, instead coinciding with intrahepatic type I IFN responses. Thus, viral RNA-induced innate immune responses regulate the antigen-processing machinery, which occurs prior to the detection of IFN-gamma at the site of infection. This mechanism may contribute to the high effectiveness (95%) of type I IFN-based therapies if administered early during HCV infection.

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Available from: Peter-Michael Kloetzel, Oct 06, 2015
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    • "However, HCV-infected cells also need to be studied in the context of interaction between effector CD8+ T-cells and target cells. In particular, the regulation of the antigen processing and presentation machineries in HCV-infected cells is of interest, including immunoproteasomes (28), proteasome activators (72), and MHC molecules. In fact, a recent study demonstrated that HCV attenuates IFN-induced expression of MHC class I molecules, which are required for the recognition of virus-infected cells by CD8+ T-cells. "
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    ABSTRACT: Hepatitis C virus (HCV) infects approximately 170 million people worldwide and is a major cause of life-threatening liver diseases such as liver cirrhosis and hepatocellular carcinoma. Acute HCV infection often progresses to chronic persistent infection, although some patients recover spontaneously. The divergent outcomes of acute HCV infection are known to be determined by differences in virus-specific T-cell responses among patients. Of the two major T-cell subsets, CD8(+) T-cells are known to be the key effector cells that control viral infections via cytolytic activity and cytokine secretion. Herein, we review various aspects of HCV-specific CD8(+) T-cell responses in acute HCV infection. In particular, we focus on timing of CD8(+) T-cell responses, relationship between CD8(+) T-cell responses and outcomes of acute HCV infection, receptor expression on CD8(+) T-cells, breadth of CD8(+) T-cell responses, and viral mutations.
    Frontiers in Immunology 06/2014; 5:266. DOI:10.3389/fimmu.2014.00266
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    • "The activation of PRR induces the production of large amount of proinflammationary cytokines, such as type I IFNs and IFNγ [12], [13], resulting in a Th1 immune response. As a major cytokine in many viral infections, IFNγ upregulates the expression of MHC class I [14] and three immunoproteasome subunits β1i (LMP2), β2i (MECL-1), and β5i (LMP7), which replace their constitutive counterparts, β1, β2, and β5 [15], [16], and consequently increases the activity of the MHC I antigen presentation pathway [17]. In addition, we reported previously that Delta-24-RGD induces autophagy and consequent cell lysis [9], [18]. "
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    ABSTRACT: Emerging evidence suggests anti-cancer immunity is involved in the therapeutic effect induced by oncolytic viruses. Here we investigate the effect of Delta-24-RGD oncolytic adenovirus on innate and adaptive anti-glioma immunity. Mouse GL261-glioma model was set up in immunocompetent C57BL/6 mouse for Delta-24-RGD treatment. The changes of the immune cell populations were analyzed by immunohistochemistry and flow cytometry. The anti-glioma immunity was evaluated with functional study of the splenocytes isolated from the mice. The efficacy of the virotherapy was assessed with animal survival analysis. The direct effect of the virus on the tumor-associated antigen presentation to CD8+ T cells was analyzed with an in vitro ovalbumin (OVA) modeling system. Delta-24-RGD induced cytotoxic effect in mouse glioma cells. Viral treatment in GL261-glioma bearing mice caused infiltration of innate and adaptive immune cells, instigating a Th1 immunity at the tumor site which resulted in specific anti-glioma immunity, shrunken tumor and prolonged animal survival. Importantly, viral infection and IFNγ increased the presentation of OVA antigen in OVA-expressing cells to CD8+ T-cell hybridoma B3Z cells, which is blocked by brefeldin A and proteasome inhibitors, indicating the activity is through the biosynthesis and proteasome pathway. Our results demonstrate that Delta-24-RGD induces anti-glioma immunity and offers the first evidence that viral infection directly enhances presentation of tumor-associated antigens to immune cells.
    PLoS ONE 05/2014; 9(5):e97407. DOI:10.1371/journal.pone.0097407 · 3.23 Impact Factor
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    • "In line with the induction of ISGs by HCV infection itself enhanced transcription of ISGs in acutely and chronically HCV-infected chimpanzees as well as chronically infected patients has been observed. Importantly, the subsets of upregulated ISGs detected in vivo overlap to a large degree with those detected in IFN-treated cell cultures in in vitro [10] [11] [47] [48] [51] [67] [68] "
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    ABSTRACT: Infections with the hepatitis C virus (HCV) are a major cause of chronic liver disease. While the acute phase of infection is mostly asymptomatic, this virus has the high propensity to establish persistence and in the course of one to several decades liver disease can develop. HCV is a paradigm for the complex interplay between the interferon (IFN) system and viral countermeasures. On one hand HCV induces an IFN response, but on the other hand within the infected cell HCV is rather sensitive against the antiviral state triggered by IFNs. Numerous IFN-stimulated genes (ISGs) have been reported to suppress HCV replication, but in only a few cases we begin to understand the molecular mechanisms underlying antiviral activity. It is becoming increasingly clear that blockage of viral replication is mediated by the concerted action of multiple ISGs that target different steps of the HCV replication cycle. This review briefly summarizes the activation of the IFN system by HCV and then focuses on ISGs targeting the HCV replication cycle and their possible mode of action.
    Journal of Hepatology 08/2013; 59(6). DOI:10.1016/j.jhep.2013.07.033 · 11.34 Impact Factor
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