title: Gamma-interferon-inducible, lysosome/endosome-localized thiolreductase, GILT, has anti-retroviral activity and its expression is counteracted by HIV-1.
abstract: The mechanism by which type II interferon (IFN) inhibits virus replications remains to be identified. Murine leukemia virus (MLV) replication was significantly restricted by γ-IFN, but not human immunodeficiency virus type 1 (HIV-1) replication. Because MLV enters host cells via endosomes, we speculated that certain cellular factors among γ-IFN-induced, endosome-localized proteins inhibit MLV replication. We found that γ-IFN-inducible lysosomal thiolreductase (GILT) significantly restricts HIV-1 replication as well as MLV replication by its thiolreductase activity. GILT silencing enhanced replication-defective HIV-1 vector infection and virion production in γ-IFN-treated cells, although γ-IFN did not inhibit HIV-1 replication. This result showed that GILT is required for the anti-viral activity of γ-IFN. Interestingly, GILT protein level was increased by γ-IFN in uninfected cells and env-deleted HIV-1-infected cells, but not in full-length HIV-1-infected cells. γ-IFN-induced transcription from the γ-IFN-activation sequence was attenuated by the HIV-1 Env protein. These results suggested that the γ-IFN cannot restrict HIV-1 replication due to the inhibition of γ-IFN signaling by HIV-1 Env. Finally, we found that 4,4'-dithiodipyridine (4-PDS), which inhibits S-S bond formation at acidic pH, significantly suppresses HIV-1 vector infection and virion production, like GILT. In conclusion, this study showed that GILT functions as a host restriction factor against the retroviruses, and a GILT mimic, 4-PDS, is the leading compound for the development of novel concept of anti-viral agents.
authors.affiliation: Division of Cytokine Signaling, Graduate School of Medical Sciences, Nagasaki University, Nagasaki, Japan.|Department of AIDS Research, Institute of Tropical Medicine, G-COE, Nagasaki University, Nagasaki, Japan.
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Kubo
authors.affiliation: Division of Cytokine Signaling, Graduate School of Medical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Izumida
authors.affiliation: Division of Cytokine Signaling, Graduate School of Medical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Yashima
authors.affiliation: Division of Cytokine Signaling, Graduate School of Medical Sciences, Nagasaki University, Nagasaki, Japan.|Department of AIDS Research, Institute of Tropical Medicine, G-COE, Nagasaki University, Nagasaki, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Yoshii-Kamiyama
authors.affiliation: Department of Immunology, Graduate School and Faculty of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Yuetsu
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Division of Cytokine Signaling, Graduate School of Medical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yasui
authors.affiliation: Division of Cytokine Signaling, Graduate School of Medical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Hayashi
authors.affiliation: Division of Cytokine Signaling, Graduate School of Medical Sciences, Nagasaki University, Nagasaki, Japan.|Present address: Department of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Matsuyama
mesh_terms: D000818:Animals; D044966:Anti-Retroviral Agents / Q000494:pharmacology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D004228:Dithionitrobenzoic Acid / Q000494:pharmacology; D015686:Gene Products, env / Q000502:physiology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D009052:Leukemia Virus, Murine / Q000187:drug effects / Q000502:physiology; D051379:Mice; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000502:physiology*; D060149:Tetraspanin 30 / Q000502:physiology; D014771:Virion / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D044966:Anti-Retroviral Agents; D015686:Gene Products, env; D060149:Tetraspanin 30; D007371:Interferon-gamma; D004228:Dithionitrobenzoic Acid; C056859:IFI30 protein, human; D050862:Oxidoreductases Acting on Sulfur Group Donors
keywords: antiviral; endosome; gamma-interferon; retroviruses; thiolreductase