Interferon (IFN)-Ξ±, -Ξ² and -Ξ³ have been shown to be only marginally effective against severe acute respiratory syndrome coronavirus (SARS-CoV) replication in Vero cell lines. We investigated the combination of type I IFNs (IFN-Ξ± or -Ξ²) and IFN-Ξ³ for antiviral activity and found that such combinations synergistically inhibited SARS-CoV replication in Vero cells, using yield reduction assay and the isobologram and combination index methods of Chou and Talalay for evaluation. The highly synergistic anti-SARS-CoV action of type I IFNs and IFN-Ξ³ parallels the marked increase in 2β€²-5β€²-oligoadenylate synthetase and p56 mRNAs following exposure in Vero cells to either IFN-Ξ± or -Ξ² and IFN-Ξ³ compared with the transcriptional levels obtained after stimulation with either IFN alone. These results demonstrate that SARS-CoV, although only moderately sensitive to the antiviral action of the individual types of IFN, is highly sensitive to a combination of type I and II IFNs, which suggests that such combinations may have potential in the treatment of SARS-CoV infections. Copyright Β© 2007 S. Karger AG.