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: Yoshinao Kubo, Mai Izumida, Yuka Yashima, Haruka Yoshii-Kamiyama, Yuetsu Tanaka, Kiyoshi Yasui, Hideki Hayashi, Toshifumi Matsuyama
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 44 Pg. 71255-71273 (Nov 01 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27655726 (Publication Type: Journal Article)

Chemical References

• Anti-Retroviral Agents
• Gene Products, env
• Tetraspanin 30
• Interferon-gamma
• Dithionitrobenzoic Acid
• IFI30 protein, human
• Oxidoreductases Acting on Sulfur Group Donors

Topics

• Animals
• Anti-Retroviral Agents (pharmacology)
• COS Cells
• Chlorocebus aethiops
• Dithionitrobenzoic Acid (pharmacology)
• Gene Products, env (physiology)
• HIV-1 (drug effects, physiology)
• Humans
• Interferon-gamma (pharmacology)
• Leukemia Virus, Murine (drug effects, physiology)
• Mice
• Oxidoreductases Acting on Sulfur Group Donors (physiology)
• Tetraspanin 30 (physiology)
• Virion (physiology)
• Virus Replication (drug effects)