Interferon resistance promotes oncolysis by influenza virus NS1-deletion mutants

NSI protein of influenza virus is a virulence factor that counteracts Type I interferon (IFN)-mediated antiviral response by the host. A recombinant influenza A virus that lacks the NSI protein only replicates efficiently in systems that contain defective IFN pathways. We demonstrate that the conditional replication properties of NSI-modified influenza A virus mutants can be exploited for the virus-mediated oncolysis of IFN-resistant tumor cells. IFN resistance in analyzed tumor cell lines correlated with a reduced expression of STAT I. Addition of exogenous IFNalpha or supernatant of virus-infected endothelial cells inhibited viral oncolysis in IFN-sensitive but not in IFN-resistant cell lines. The oncolytic potential of NSI-modified influenza A virus mutants could be exploited in vivo in a SCID mouse model of a subcutaneously-implanted human IFN-resistant melanoma. The data indicate that IFN-resistant tumors are a suitable target for oncolysis induced by NSI-modified influenza virus mutants. STAT I might serve as a marker to identify these IFN-resistant tumors. (C) 2004 Wiley-Liss, Inc.