Interferon resistance promotes oncolysis by influenza virus NS1-deletion mutants.
NS1 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 NS1 protein only replicates efficiently in systems that contain defective IFN pathways. We demonstrate that the conditional replication properties of NS1-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 STAT1. 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 NS1-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 NS1-modified influenza virus mutants. STAT1 might serve as a marker to identify these IFN-resistant tumors.
Muster
Thomas
T
Department of Dermatology, University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
Rajtarova
Julia
J
Sachet
Monika
M
Unger
Hermann
H
Fleischhacker
Reinhard
R
Romirer
Ingrid
I
Grassauer
Andreas
A
Url
Angelika
A
García-Sastre
Adolfo
A
Wolff
Klaus
K
Pehamberger
Hubert
H
Bergmann
Michael
M
D000818:Animals; D002455:Cell Division; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000032:analysis; D019008:Drug Resistance, Neoplasm; D017353:Gene Deletion; D006801:Humans; D007372:Interferons / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000628:therapy* / Q000821:virology; D009975:Orthomyxoviridae / Q000235:genetics*; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000032:analysis; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D014779:Virus Replication
D004268:DNA-Binding Proteins; C085820:INS1 protein, influenza virus; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D017361:Viral Nonstructural Proteins; D007372:Interferons