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 ?-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 ?-IFN-induced, endosome-localized proteins inhibit MLV replication. We found that ?-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 ?-IFN-treated cells, although ?-IFN did not inhibit HIV-1 replication. This result showed that GILT is required for the anti-viral activity of ?-IFN. Interestingly, GILT protein level was increased by ?-IFN in uninfected cells and env-deleted HIV-1-infected cells, but not in full-length HIV-1-infected cells. ?-IFN-induced transcription from the ?-IFN-activation sequence was attenuated by the HIV-1 Env protein. These results suggested that the ?-IFN cannot restrict HIV-1 replication due to the inhibition of ?-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.

SUBMITTER: Kubo Y 

PROVIDER: S-EPMC5342076 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature