Human Cytomegalovirus Blocks Tumor Necrosis Factor Alpha- and Interleukin-1β-Mediated NF-κB Signaling

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Abstract
NF-κB plays an important role in the early cellular response to pathogens by activating genes involved in inflammation, immune response, and cell proliferation and survival. NF-κB is also utilized by many viral pathogens, like human cytomegalovirus (HCMV), to activate their own gene expression programs, reflecting intricate roles for NF-κB in both antiviral defense mechanisms and viral physiology. Here we show that the NF-κB signaling pathway stimulated by proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) becomes inhibited in HCMV-infected cells. The block to NF-κB signaling is first noticeable during the early phase of infection but is fully established only at later times. Biochemical and genetic evidence demonstrates that the viral inhibition of proinflammatory signaling by distinct cytokines occurs upstream of the convergence point of NF-κB-activating pathways, i.e., the IκB kinase complex, and that it is mediated via different mechanisms. Consistent with this, we further show that an HCMV variant that has lost the ability to downregulate TNF-α-induced NF-κB signaling also fails to downregulate surface expression of TNF receptor 1, thereby mechanistically linking the inhibition of TNF-α-induced NF-κB signaling by HCMV to TNF receptor targeting. Our data support a model whereby HCMV inhibits cytokine-induced NF-κB signaling at later times during infection, and we suggest that this contributes to the inhibition of the cell9s antiviral defense program.