Grant: Operating Grant

While some viruses are harmful, other viruses provide safe and innovative tools to deliver therapeutic genes or selectively kill cancer cells. Mammalian orthoreovirus (reovirus) infects most individuals through the intestine but is non-pathogenic. Reovirus replicates preferentially in cancer cells relative to healthy cells, thus offering a promising oncotherapy. For reasons poorly understood, over 99 percent of reovirus particles fail to establish infection, even in cancer cells. Our program explores factors that impact reovirus infectivity and can be fine-tuned to improve reovirus oncotherapy. We recently isolated two reovirus mutants with higher infectivity towards many cancer cells. These 'next-generation' reovirus mutants prolong survival in a mouse model of melanoma, indicating that tumour clearance can be improved by increasing reovirus infectivity towards cancer cells. We also discovered that specific mutations in two reovirus proteins, sigma 1 and lambda 2, account for improved oncolysis by the reovirus mutants. Our project will discover precisely how these mutations promote infectivity of reovirus particles. We hypothesize that these mutations help reovirus disassemble when it enters a cells. We will therefore explore the effects of sigma 1 and lambda 2 mutations on reovirus disassembly and identify critical protein domains that promote successful reovirus disassembly in cancer cells. We also hypothesize that mutations in sigma 1 and lambda 2 that promote infection of cancer cells concurrently make reovirus less stable in the intestine, which is the natural route for reovirus infection. Our project will therefore evaluate if next-generation reovirus mutants are weakened towards the intestine, and therefore present a safer alternative to wild-type reovirus. Overall, our studies will reveal new mechanisms that impact infectivity of reovirus particles towards tumor cells and will help us understand how to improve reovirus cancer therapy.