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

// Yoshinao Kubo 1,2 , Mai Izumida 1 , Yuka Yashima 1 , Haruka Yoshii-Kamiyama 1,2 , Yuetsu Tanaka 3 , Kiyoshi Yasui 1 , Hideki Hayashi 1 and Toshifumi Matsuyama 1,4 1 Division of Cytokine Signaling, Graduate School of Medical Sciences, Nagasaki University, Nagasaki, Japan 2 Department of AIDS Research, Institute of Tropical Medicine, G-COE, Nagasaki University, Nagasaki, Japan 3 Department of Immunology, Graduate School and Faculty of Medicine, University of the Ryukyus, Okinawa, Japan 4 Present address: Department of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA Correspondence to: Toshifumi Matsuyama, email: // Keywords : gamma-interferon, antiviral, endosome, retroviruses, thiolreductase Received : June 11, 2016 Accepted : August 26, 2016 Published : September 18, 2016 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.