Designing and building oncolytic viruses

Maroun, Justin; Muñoz-Alía, Miguel; Ammayappan, Arun; Schulze, Autumn; Peng, Kah-Whye; Russell, Stephen

Polymerase infidelity is not the sole driver of virus genome diversification and evolution. For many viruses, recombination between homologous viral genomes can occur when two related viruses infect the same cell [178] . This type of recombination is not a feature of negative strand RNA virus evolution because the nascent progeny viral genomes are cotranscriptionally incorporated into a helical ribonucleocapsid structure which prevents recombination. However, for positive sense RNA picornaviruses, and DNA viruses such as adenovirus, HSV and vaccinia, it is important to consider the possibility that the input virus may encounter and recombine with a homologous 'wild-type' virus in a treated patient. While such recombination has never been documented in OV trials, there are well described examples in the field of vaccinology, such as the re-emergence of pathogenic polioviruses through the recombination of vaccine genomes and naturally circulating picornavirus genomes [179] . In view of these risks, it is generally considered inadvisable to arm viruses with therapeutic transgenes that have theoretical potential to increase pathogenicity if transferred to a related naturally circulating virus. Genes encoding immunosuppressive, antiapoptotic or directly cytotoxic proteins are on this list.