Journal
JOURNAL OF INNATE IMMUNITY
Volume 2, Issue 6, Pages 607-617Publisher
KARGER
DOI: 10.1159/000317690
Keywords
Hepatitis C virus; B cells; Retinoic acid-inducible gene-I; Interferon promoter-stimulator-1; Interferon regulatory factor-3; Interferon beta
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Funding
- Ministry of Health, Labour and Welfare, Japan
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A recent study by our group indicated that peripheral B cells in chronic hepatitis C (CHC) patients are infected with hepatitis C virus (HCV). This raised the logical question of how HCV circumvents the antiviral immune responses of B cells. Because type I interferon (IFN) plays a critical role in the innate antiviral immune response, IFN beta expression levels in peripheral B cells from CHC patients were analyzed, and these levels were found to be comparable to those in normal B cells, which suggested that HCV infection failed to trigger antiviral immune responses in B cells. Sensing mechanisms for invading viruses in host immune cells involve Toll-like receptor-mediated and retinoic acid-inducible gene-I (RIG-I)-mediated pathways. Both pathways culminate in IFN regulatory factor-3 (IRF-3) translocation into the nucleus for IFN beta gene transcription. Although the expression levels of RIG-I and its adaptor molecule, IFN promoter-stimulator-1, were substantially enhanced in CHC B cells, dimerization and subsequent nuclear translocation of IRF-3 were not detectable. TANK-binding kinase-1 (TBK1) and I kappa B kinase epsilon (IKK epsilon) are essential for IRF-3 phosphorylation. Constitutive expression of both kinases was markedly enhanced in CHC B cells. However, reduced expression of heat shock protein of 90 kDa, a TBK1 stabilizer, and enhanced expression of SIKE, an IKK epsilon suppressor, were observed in CHC B cells, which might suppress the kinase activity of TBK1/IKK epsilon for IRF-3 phosphorylation. In addition, the expression of vesicle-associated membrane protein-associated protein-C, a putative inhibitor of HCV replication, was negligible in B cells. These results strongly suggest that HCV utilizes B cells as a reservoir for persistent infection. Copyright (C) 2010 S. Karger AG, Basel
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