Role of Interferon-Stimulated Gene ISG-15 in the Interferon-ω-Mediated Inhibition of Human Immunodeficiency Virus Replication

Interferon-α (IFN-α) inhibits human immunodeficiency virus (HIV) replication in vivo and in vitro. In this study, we show that IFN-ω (IFN-ω) is also a potent inhibitor of HIV replication in vitro and that both laboratory and primary isolates of HIV-1 are more sensitive to IFN-ω than to IFN-α2. Like IFN-α2, IFN-ω inhibited proviral synthesis in acutely infected cells, but in contrast to IFN-α2, IFN-ω did not alter the levels of HIV-1 unspliced messages. Yet, inhibition of HIV protein synthesis was greater in IFN-ω-treated than in IFN-α2-treated cells. Whereas expression of IFN-stimulated genes was transient in IFN-α2-treated cells, their expression was sustained in IFN-ω-treated cells. Expression of ISG-15 in particular was higher on treatment with IFN-ω than with IFN-α2. Overexpression of ISG-15 in IFN-α2-treated cells mimicked the effects of IFNω In untreated cells, it resulted in the trapping of HIV unspliced RNA in the nucleus and a decrease in cytoplsmic HIV transcripts and HIV protein synthesis. These findings suggest that the sustained induction of IFN-stimulated genes by IFN-ωand that of ISG-15 in particular may confer a higher therapeutic index to IFN-ωin controlling HIV infection.