Gamma-interferon-inducible, lysosome/endosome-localized thiolreductase, GILT, has anti-retroviral activity and its expression is counteracted by HIV-1

• Published in: Oncotarget 2016-11, Vol.7 (44), p.71255-71273
• Main Authors: Kubo, Yoshinao, Izumida, Mai, Yashima, Yuka, Yoshii-Kamiyama, Haruka, Tanaka, Yuetsu, Yasui, Kiyoshi, Hayashi, Hideki, Matsuyama, Toshifumi
• Format: Article
• Language: English
• Subjects: Animals; Anti-Retroviral Agents - pharmacology; Cercopithecus aethiops; COS Cells; Dithionitrobenzoic Acid - pharmacology; Gene Products, env - physiology; HIV-1 - drug effects; HIV-1 - physiology; Humans; Interferon-gamma - pharmacology; Leukemia Virus, Murine - drug effects; Leukemia Virus, Murine - physiology; Mice; Oxidoreductases Acting on Sulfur Group Donors - physiology; Research Paper; Tetraspanin 30 - physiology; Virion - physiology; Virus Replication - drug effects
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.12104

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.