title: Peripheral B cells may serve as a reservoir for persistent hepatitis C virus infection.
abstract: 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, IFNβ 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 IFNβ 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 IκB kinase ε (IKKε) 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 IKKε suppressor, were observed in CHC B cells, which might suppress the kinase activity of TBK1/IKKε 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.
authors: Department of Research on Blood and Biological Products, National Institute of Infectious Diseases, Tokyo, Japan.
authors: Masahiko
authors: M
authors: Ito
authors: Atsuko
authors: A
authors: Masumi
authors: Keiko
authors: K
authors: Mochida
authors: Hiroshi
authors: H
authors: Kukihara
authors: Kohji
authors: K
authors: Moriishi
authors: Yoshiharu
authors: Y
authors: Matsuura
authors: Kazunari
authors: K
authors: Yamaguchi
authors: Toshiaki
authors: T
authors: Mizuochi
mesh_terms: D021581:Active Transport, Cell Nucleus; D000368:Aged; D018941:Antigens, CD19 / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D002467:Cell Nucleus / Q000378:metabolism*; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D004197:Disease Reservoirs / Q000821:virology; D005786:Gene Expression Regulation; D016174:Hepacivirus / Q000276:immunology* / Q000472:pathogenicity; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000821:virology; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D057131:Immune Evasion; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism*; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000276:immunology
chemical_list: D018941:Antigens, CD19; D050838:Interferon Regulatory Factor-3; D011971:Receptors, Immunologic; D016899:Interferon-beta; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D051550:I-kappa B Kinase; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases