The IκB kinases restrict human cytomegalovirus infection.

Human Cytomegalovirus (HCMV) is a ubiquitous herpesvirus that causes disease in immunosuppressed populations. HCMV has a complex relationship with innate immune signaling pathways. Specifically, HCMV has been found to block some aspects of inflammatory signaling while benefiting from others. Through analysis of knockout cell lines targeting the NFκB regulatory kinases IKKα and IKKβ, we find that the IKK kinases are host restriction factors that contribute to cytokine-mediated resistance to viral infection, limit the initiation of HCMV infection, and attenuate viral cell-to-cell spread. The HCMV UL 26 protein is a viral immune modulator important for HCMV infection that has been shown to inhibit host cell NFκB signaling, yet it has remained unclear how UL 26-mediated NFκB modulation contributes to infection. Here, we find that UL 26's modulation of NFκB signaling is separable from its contribution to high-titer viral replication. However, we find that IKKβ is required for the induction of cytokine expression associated with ΔUL 26 infection. Collectively, our data indicate that the IKK kinases restrict infection, but that HCMV targets their signaling to modulate the cellular inflammatory environment. Importance Innate immune signaling is a critical defense against virus infection, and represents a central host-virus interaction that frequently determines the outcome of infection. NFκB signaling is an essential component of innate immunity that is extensively modulated by HCMV, a significant cause of morbidity in neonates and the immunosuppressed. However, the roles that various facets of NFκB signaling play during HCMV infection have remained elusive. We find that the two major regulatory kinases in this pathway, IKKα and IKKβ, limit the initiation of infection, viral replication, and cell-to-cell spread. In addition, our results indicate that these kinases contribute differently to the host cell response to infection in the absence of a virally encoded NFκB inhibitor, UL 26. Given its importance to viral infection, elucidating the contributions of various NFκB constituents to infection is an essential first step towards the possibility of targeting this pathway therapeutically.