Mammalian orthoreovirus can exit cells in extracellular vesicles.

The exit strategy that many viruses use to escape cells is unknown. Reovirus is a nonenveloped human virus and an ideal model system to understand virus exit strategies and their inluence on infection. We found that two different reovirus strains, one that disrupts cell membranes and one that leaves cells largely intact, increase the release of extracellular vesicles (EVs) from cells. Both reovirus strains are released from cells as free particles and in association with EVs, which are membrane-bound structures that function in cell-to-cell communication. Depending on cell type and virus type, EVs can act like an 'invisibility cloak' that shields reovirus from antibodies. EVs can also bundle and ferry reovirus particles between cells. Although we used cells to examine the effects of reovirus association with EVs, it is possible that in mammalian hosts, EVs may shield reovirus from immune defenses and promote more efficient transmission and infection through a 'strength-in-numbers' strategy. Future work building on these findings will test the biological significance of EV-enclosed reovirus and may inform delivery strategies for oncolytic reoviruses to tumor sites. Broadly, these findings enhance our understanding of virus egress strategies and infection principles that may apply to other viruses that travel in EVs.