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
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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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