title: Indoleamine 2,3-dioxygenase mediates the antiviral effect of gamma interferon against hepatitis B virus in human hepatocyte-derived cells.
abstract: Alpha interferon (IFN-α) is an approved medication for chronic hepatitis B. Gamma interferon (IFN-γ) is a key mediator of host innate and adaptive antiviral immunity against hepatitis B virus (HBV) infection in vivo. In an effort to elucidate the antiviral mechanism of these cytokines, 37 IFN-stimulated genes (ISGs), which are highly inducible in hepatocytes, were tested for their ability to inhibit HBV replication upon overexpression in human hepatoma cells. One ISG candidate, indoleamine 2,3-dioxygenase (IDO), an IFN-γ-induced enzyme catalyzing tryptophan degradation, efficiently reduced the level of intracellular HBV DNA without altering the steady-state level of viral RNA. Furthermore, expression of an enzymatically inactive IDO mutant did not inhibit HBV replication, and tryptophan supplementation in culture completely restored HBV replication in IDO-expressing cells, indicating that the antiviral effect elicited by IDO is mediated by tryptophan deprivation. Interestingly, IDO-mediated tryptophan deprivation preferentially inhibited viral protein translation and genome replication but did not significantly alter global cellular protein synthesis. Finally, tryptophan supplementation was able to completely restore HBV replication in IFN-γ- but not IFN-α-treated cells, which strongly argues that IDO is the primary mediator of IFN-γ-elicited antiviral response against HBV in human hepatocyte-derived cells.
authors.affiliation: Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, 3805 Old Easton Road, Doylestown, PA 18902, USA.
authors.forename: Richeng
authors.initials: R
authors.lastname: Mao
authors.forename: Jiming
authors.initials: J
authors.lastname: Zhang
authors.forename: Dong
authors.initials: D
authors.lastname: Jiang
authors.forename: Dawei
authors.initials: D
authors.lastname: Cai
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Levy
authors.forename: Andrea
authors.initials: A
authors.lastname: Cuconati
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Block
authors.forename: Ju-Tao
authors.initials: JT
authors.lastname: Guo
authors.forename: Haitao
authors.initials: H
authors.lastname: Guo
mesh_terms: D045744:Cell Line, Tumor; D003470:Culture Media / Q000737:chemistry; D004279:DNA, Viral / Q000378:metabolism; D015870:Gene Expression; D006515:Hepatitis B virus / Q000254:growth & development / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology* / Q000821:virology*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000172:deficiency / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology*; D009154:Mutation; D012367:RNA, Viral / Q000378:metabolism; D014364:Tryptophan / Q000378:metabolism; D014779:Virus Replication
chemical_list: D003470:Culture Media; D004279:DNA, Viral; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D012367:RNA, Viral; D007371:Interferon-gamma; D014364:Tryptophan