Virus-induced apoptosis is thought to be the primary mechanism of cell death 
following reovirus infection. Induction of cell death following reovirus 
infection is initiated by the incoming viral capsid proteins during cell entry 
and occurs via NF-κB-dependent activation of classical apoptotic pathways. 
Prototype reovirus strain T3D displays a higher cell-killing potential than 
strain T1L. To investigate how signaling pathways initiated by T3D and T1L 
differ, we methodically analyzed cell death pathways activated by these two 
viruses in L929 cells. We found that T3D activates NF-κB, initiator caspases, 
and effector caspases to a significantly greater extent than T1L. Surprisingly, 
blockade of NF-κB or caspases did not affect T3D-induced cell death. Cell death 
following T3D infection resulted in a reduction in cellular ATP levels and was 
sensitive to inhibition of the kinase activity of receptor interacting protein 1 
(RIP1). Furthermore, membranes of T3D-infected cells were compromised. Based on 
the dispensability of caspases, a requirement for RIP1 kinase function, and the 
physiological status of infected cells, we conclude that reovirus can also 
induce an alternate, necrotic form of cell death described as necroptosis. We 
also found that induction of necroptosis requires synthesis of viral RNA or 
proteins, a step distinct from that necessary for the induction of apoptosis. 
Thus, our studies reveal that two different events in the reovirus replication 
cycle can injure host cells by distinct mechanisms.
IMPORTANCE: Virus-induced cell death is a determinant of pathogenesis. Mammalian 
reovirus is a versatile experimental model for identifying viral and host 
intermediaries that contribute to cell death and for examining how these factors 
influence viral disease. In this study, we identified that in addition to 
apoptosis, a regulated form of cell death, reovirus is capable of inducing an 
alternate form of controlled cell death known as necroptosis. Death by this 
pathway perturbs the integrity of host membranes and likely triggers 
inflammation. We also found that apoptosis and necroptosis following viral 
infection are activated by distinct mechanisms. Our results suggest that host 
cells can detect different stages of viral infection and attempt to limit viral 
replication through different forms of cellular suicide. While these death 
responses may aid in curbing viral spread, they can also exacerbate tissue 
injury and disease following infection.