Designing and building oncolytic viruses

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

Understanding the selective pressures that operate within the tumor and the host, as well as the role of viral quasispecies in treatment outcomes is an active area of research. RNA and DNA viruses exist as a population of quasispecies or collections of related viral genomes undergoing variation and selective pressure [174] . Generation of quasispecies occurs when viral genomes are copied during the replication cycle. Viral polymerases typically have an error rate that introduces an average of one or more base mutations per progeny genome [175] . In general, the larger the virus genome, the lower the polymerase error rate. Picornaviruses are among the smallest viruses being developed for oncolytic therapy with positive sense RNA genomes ranging from 7 to 9 kb in length, and their RNA polymerases have a correspondingly high intrinsic error rate. Production of a virus for clinical application is a highly regulated process and involves multiple rounds of replication to achieve enough virus for patients. The viral product is therefore already a swarm of quasispecies at the time it is administered to the patient and mutates further as it undergoes additional rounds of replication in vivo. Studies of the mutation rates of viral polymerases, the generation of quasi species, the evolution of viral populations and the evolution between dominant subspecies within a virus population are therefore of great interest and relevance to the OV field.