Designing and building oncolytic viruses

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

For a virus to be 'successful' it must combat these host cell responses, avoiding detection, as long as possible, for suppressing the establishment of an antiviral state and preventing apoptosis. Virtually all naturally occurring viruses therefore encode proteins that inhibit apop tosis and the antiviral state [108] . Removing these accessory functions from the viral genome leads to virus attenuation in normal tissues, but to a much lesser degree in cancerous tissues. This is because cancer cells are intrinsically resistant to apoptosis and to the establishment of an antiviral state, making them highly susceptible to attenuated viruses that are no longer able to control those processes. This has provided a mechanistic basis for physiologic targeting of several viruses; VSV by mutating the matrix gene whose encoded protein blocks the interferon response [109] ; HSV by mutating both copies of the γ-34.5 gene which interferes with interferonmediated shutoff of host protein synthesis and enhances neurovirulence [110, 111] ; adenovirus by mutating the E1B protein, one of whose actions is to inhibit the apoptotic activity of p53 [112] .