Designing and building oncolytic viruses

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

Fusion of the lipid envelope of an incoming virus with the limiting membrane of its target cell is a necessary step in the life cycle of an enveloped virus, to deliver the encapsidated viral genome into the target cell cytoplasm. This virus-to-cell fusion reaction is mediated by FMGs embedded in the envelope of the virus, and may occur at the cell surface at neutral pH, or in the endo-somal compartment at acidic pH [150] . Neutral pH fusion is triggered by receptor attachment. Cells expressing certain virally encoded, neutral pH-active FMGs on their surface may fuse with neighboring receptor positive cells (cell-to-cell fusion), giving rise to multinucleated syncytia, the hallmark cytopathic signature of a fusogenic virus (e.g., measles) [151] . But more often the FMG is activated only after its incorporation into a budding virus particle, so cannot cause cell-tocell fusion, and must be modified, for example, by cytoplasmic tail truncation, to render it constitutively fusogenic. Either way, FMG-driven fusion of OV-infected cells with uninfected neighboring cells leads to increased bystander killing because multinucleated syncytia are nonviable as well as being highly immunogenic [152] . Based on these observations, nonfusogenic OVs have been armed with FMGs thereby conferring superior oncolytic potency [123, 153] . In one example, an oncolytic herpes virus was rendered highly fusogenic when engineered to encode a cytoplasmically truncated gibbon ape leukemia virus envelope glycoprotein [154] [155] [156] while in another study, an oncolytic VSV was rendered highly fusogenic by replacing its surface glycoprotein (G) with the hemagglutinin and fusion glycoproteins of measles virus.