Summary Cytomegalovirus (CMV, a b-herpesvirus) establishes a persistent infection that is endemic in humans and mice. CMV causes acute clinical disease only if immunity is naïve or compromised, exemplifying how coevolution with its host over millennia has resulted in a largely non-pathogenic détente. The nature of this détente is dependent upon the many strategies that CMV uses to subvert detection by the immune system. TNF-related cytokines are key regulators of antiviral defenses, and we have shown that both mouse and human CMV (MCMV and HCMV) inhibit expression of the TNF-related apoptosis inducing ligand death-receptors (TRAIL-DR) via the M166 and UL141 viral proteins, respectively. Viral mutants lacking these proteins are highly sensitive to control by TRAIL-expressing innate immune cells during the early-phase of CMV infection. In contrast, if MCMV is unable to restrict TRAIL-DR signaling via M166, the duration of persistent replication is dramatically longer. This is likely due to an altered CD4 T cell response that is unable to resolve persistence within the normal time frame. Together, our past and new results place the TRAIL signaling system at a critical apex in regulating various phases of the immune response to persistent virus infection. This proposal will reveal the how this TNF-family cytokine regulates antiviral immune defenses, and will help to define their broader importance in regulating inflammation and cell death.