ABSTRACT

The major feature typical of oncolytic viruses is their conditionally replicating phenotype, which permits them to grow in malignant cells but not in normal tissue. The recent elucida-

tion of the function of the influenza virus NS1 protein [1] gave us the possibility for a rational development of oncolytic influenza A viruses by virtue of genetic engineering. The antagonism of the cellular antiviral type I interferon (IFN) response turned out to be one of the main functions of NS1. This finding is based on the observation that influenza A viruses, which lack a functional NS1 gene, do not grow in IFN-competent systems but replicate effectively in systems that lack expression of functional IFN [2], contain defects in the Jak/STAT (signal transducer and activator of transcription) pathway [3], or lack expression or activation of the IFN-induced, dsRNA activated protein kinase (PKR) [4]. The link between influenza A virus NS1-deletion viruses and oncolysis derives from the observation that tumor cells frequently contain defects in the IFN pathway [5] as well as in PKR activation [6]. As a consequence, NS1-deletion mutants are capable of selectively destroying such tumor cells. This renders genetically engineered NS1-deletion viruses prototypes for oncolytic influenza A virus strains. Developments that led to genetically modified oncolytic influenza virus strains, the general biology of the virus, its interactions with the IFN system, and the required characteristics of the target tumor are described in this chapter.