Role of interferon-stimulated gene ISG-15 in the interferon-omega-mediated inhibition of human immunodeficiency virus replication.
Interferon-alpha (IFN-alpha) inhibits human immunodeficiency virus (HIV) replication in vivo and in vitro. In this study, we show that IFN-omega (IFN-omega) 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-omega than to IFN-alpha 2. Like IFN-alpha 2, IFN-omega inhibited proviral synthesis in acutely infected cells, but in contrast to IFN-alpha 2, IFN-omega did not alter the levels of HIV-1 unspliced messages. Yet, inhibition of HIV protein synthesis was greater in IFN-omega-treated than in IFN-alpha 2-treated cells. Whereas expression of IFN-stimulated genes was transient in IFN-alpha 2-treated cells, their expression was sustained in IFN-omega-treated cells. Expression of ISG-15 in particular was higher on treatment with IFN-omega than with IFN-alpha 2. Overexpression of ISG-15 in IFN-alpha 2-treated cells mimicked the effects of IFN-omega. In untreated cells, it resulted in the trapping of HIV unspliced RNA in the nucleus and a decrease in cytoplasmic HIV transcripts and HIV protein synthesis. These findings suggest that the sustained induction of IFN-stimulated genes by IFN-omega and that of ISG-15 in particular may confer a higher therapeutic index to IFN-omega in controlling HIV infection.
Künzi
M S
MS
Oncology Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Pitha
P M
PM
D000998:Antiviral Agents / Q000494:pharmacology*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D006678:HIV / Q000502:physiology*; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D013268:Stimulation, Chemical; D014779:Virus Replication / Q000235:genetics*
D000998:Antiviral Agents; D007370:Interferon Type I; D011500:Protein Synthesis Inhibitors; D011994:Recombinant Proteins; C063743:interferon omega 1