title: Antiviral and Immunoregulatory Effects of Indoleamine-2,3-Dioxygenase in Hepatitis C Virus Infection.
abstract: In patients with hepatitis C virus (HCV) infection, enhanced activity of indoleamine-2,3-dioxygenase 1 (IDO) has been reported. IDO - a tryptophan-catabolizing enzyme - has been considered as both an innate defence mechanism and an important regulator of the immune response. The molecular mechanism of IDO induction in HCV infection and its role in the antiviral immune response remain unknown. Using primary human hepatocytes, we show that HCV infection stimulates IDO expression. IDO gene induction was transient and coincided with the expression of types I and III interferons (IFNs) and IFN-stimulated genes in HCV-infected hepatocytes. Overexpression of hepatic IDO prior to HCV infection markedly impaired HCV replication in hepatocytes, suggesting that IDO limits the spread of HCV within the liver. siRNA-mediated IDO knock-down revealed that IDO functions as an IFN-mediated anti-HCV effector. Hepatic IDO was most potently induced by IFN-x03B3;, and ongoing HCV replication could significantly upregulate IDO expression. IRF1 (IFN-regulatory factor 1) and STAT1 (signal transducer and activator of transcription 1) regulated hepatic IDO expression. Hepatic IDO expression also had a significant inhibitory effect on CD4+ T-cell proliferation. Our data suggest that hepatic IDO plays a dual role during HCV infection by slowing down viral replication and also regulating host immune responses.
authors: Laboratoire de Virologie, Hx00F4;pitaux Universitaires de Strasbourg, Strasbourg, France.
authors: Quentin
authors: Q
authors: Lepiller
authors: Eric
authors: E
authors: Soulier
authors: Qisheng
authors: Q
authors: Li
authors: Mélanie
authors: M
authors: Lambotin
authors: Jochen
authors: J
authors: Barths
authors: Dietmar
authors: D
authors: Fuchs
authors: Françoise
authors: F
authors: Stoll-Keller
authors: T Jake
authors: TJ
authors: Liang
authors: Heidi
authors: H
authors: Barth
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology* / Q000821:virology; D006801:Humans; D007113:Immunity, Innate; D007165:Immunosuppression Therapy; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism; D007372:Interferons / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000235:genetics
chemical_list: C576710:IDO1 protein, human; C494257:IRF1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D050856:Interferon Regulatory Factor-1; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; D007372:Interferons