Upon infection, numerous cell types secrete anti-viral cytokines that induce an anti-viral state in neighboring cells, which is critical for limiting infection. This proposal focuses on two opposing aspects of this anti-viral state: one, cytokine-induced metabolic reprogramming, which we find is essential for the ability of cytokines to limit viral infection; and two, the Human Cytomegalovirus (HCMV) UL26 protein, which we find is a major antagonist of anti-viral gene expression. HCMV is a major cause of congenital birth defects and causes severe disease in several immunosuppressed patient populations. Our results indicate that the anti-viral cytokine TNFα induces glycolytic activation, which is essential for its anti-HCMV activity. However, the mechanisms involved are not clear. We propose to identify the mechanisms through which anti-viral cytokines induce metabolic remodeling (Aim 1), and determine how cytokine-induced metabolic activities limit HCMV infection (Aim 2). Finally, we will determine how the HCMV UL26 protein blocks anti-viral responses, which we hypothesize involves modulation of the activity of an intrinsic immune transcription factor complex (Aim 3). The proposed research will identify novel cellular and viral mechanisms that govern the success of HCMV infection. These mechanisms represent key determinants that could potentially be targeted to limit virally-associated pathogenesis.