The NS1 protein of influenza virus is a virulence factor that counteracts t
he PKR-mediated antiviral response by the host. As a consequence, influenza
NS1 gene knockout virus delNS1 (an influenza A virus lacking the NS I open
reading frame) fails to replicate in normal cells but produces infectious
particles in PKR-deficient cells. Because it is known that oncogenic ras in
duces an inhibitor of PKR, we addressed the question of whether the delNS1
virus selectively replicates in cells expressing oncogenic ras. We show tha
t upon transfection and expression of oncogenic N-ras, cells become permiss
ive for productive delNS1 virus replication, suggesting that the delNS1 vir
us has specific oncolytic properties. Viral growth in the oncogenic ras-tra
nsfected cells is associated with a reduction of PKR activation during infe
ction. Moreover, treatment of s.c. established N-ras-expressing melanomas i
n severe combined immunodeficiency mice with the delNS1 virus revealed that
this virus has tumor-ablative potentials. The delNS1 virus does not replic
ate in nonmalignant cell lines such as melanocytes, keratinocytes, or endot
helial cells. The apathogenic nature of the delNS1 virus combined with the
selective replication properties of this virus in oncogenic ras-expressing
cells renders this virus an attractive candidate for the therapy of tumors
with an activated ras-signaling pathway.