Many viruses induce apoptosis via activation of host-encoded apoptosis-regulating factors. For example, the VSV M protein induces apoptosis by inhibiting the transcription of antiapoptotic factors such as Bcl-xl [52] . In other cases, virus-encoded polypeptides insert into mitochondrial membranes and trigger cytochrome c release, leading to activation of the mitochondrial apoptotic pathway. For example, influenza A virus PB1-F2 is thought to directly activate proapoptotic signaling by interaction with the mitochondrial membrane-associated factors ANT3 and VDAC1 [53] . Although one model for apoptosis induction by reovirus suggests that the w fragment of reovirus m1 protein induces apoptosis by directly targeting mitochondria analogous to PB1-F2 [13] , our studies using apoptosis-defective reovirus mutants [4, 7] , coupled with data presented here, support the idea that w-mediated NF-kB signaling activates the mitochondrial apoptotic pathway indirectly via death-receptor signaling and Bid cleavage. This indirect mechanism of mitochondrial pathway activation by a proximal signal transducer also explains the timing of prodeath signaling in the reovirus replication cycle. We think that events associated with viral entry into cells, which are mediated by the m1 w fragment subsequent to membrane penetration, activate NF-kB within 1 h of infection [7, 28] . Unlike other NF-kB agonists such as TNFa which rapidly and transiently activate NF-kB, activation of NF-kB following reovirus infection is gradual and sustained and occurs maximally at 6-8 h post infection [28] . Activated NF-kB complexes lead to expression of genes that promote cleavage-induced activation of Bid at 24-36 h post infection and elicit characteristic features of apoptosis, including effector caspase activation and DNA fragmentation. These changes occur subsequent to completion of viral replication, and, therefore, apoptosis appears to have little detectable effect on viral growth in cell culture [4, 7, 8, 28] . Although unusual, NF-kBdependent apoptotic pathways are also utilized by other viruses such as Dengue virus [54] , HIV [55] , infectious bursal disease virus [56] , and Sindbis virus [57] . Thus, our studies may have uncovered a potentially conserved signaling pathway utilized by viruses to induce apoptosis via NF-kB.