The TRAIL to viral pathogenesis: The good, the bad and the ugly

Since the discovery of Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL) in 1995, much has been learned about the protein, its receptors and signaling cascade to induce apoptosis and the regulation of its expression. However, the physiologic role or roles that TRAIL may play in vivo are still being explored. The expression of TRAIL on effector T cells and the ability of TRAIL to induce apoptosis in virally infected cells provided early clues that TRAIL may play an active role in the immune defense against viral infections. However, increasing evidence is emerging that TRAIL may have a dual function in the immune system, both as a means to kill virally infected cells and in the regulation of cytokine production. TRAIL has been implicated in the immune response to viral infections (good), and in the pathogenesis of multiple viral infections (bad). Furthermore, several viruses have evolved mechanisms to manipulate TRAIL signaling to increase viral replication (ugly). It is likely that whether TRAIL ultimately has a proviral or antiviral effect will be dependent on the specific virus and the overall cytokine milieu of the host. Knowledge of the factors that determine whether TRAIL is proviral or antiviral is important because the TRAIL system may become a target for development of novel antiviral therapies.