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

Yoshinao Kubo,Kiyoshi Yasui,Hideki Hayashi,Toshifumi Matsuyama,Haruka Yoshii-Kamiyama,Yuka Yashima,Mai Izumida,Yuetsu Tanaka

doi:10.18632/oncotarget.12104

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.

Highlights

When host cells detect viruses, the cells express the type I interferons (IFNs) including α- and β-IFNs
The treatment of TE671/CD4 cells with γ-IFN did not change the human immunodeficiency virus type 1 (HIV-1) Gag p24 amounts in the culture supernatants 3 days after the inoculation (Figure 1B). These results showed that γ-IFN restricts the Murine leukemia virus (MLV) replication, but not the HIV-1 replication
This study clearly showed that endogenous GILT functions as a host restriction factor against MLV and HIV-1

Summary

INTRODUCTION

When host cells detect viruses, the cells express the type I interferons (IFNs) including α- and β-IFNs. It has been recently reported that GBP5 induced by the type I IFNs inhibits processing and virion incorporation of the HIV-1 envelope (Env) protein [5]. We have reported that MLV infection occurs through endosomes like other enveloped viruses www.impactjournals.com/oncotarget [6], showing that endosomes are important organelles for infection by many enveloped viruses. This result prompted us to speculate that several host factors among IFN-induced, endosome-localized cellular proteins restrict MLV replication. We report here the restriction mechanisms of GILT and the counteracting machinery of HIV-1 to this host restriction factor

RESULTS

DISCUSSION

MATERIALS AND METHODS

Findings

Ethics statement