Lymphotoxins and cytomegalovirus cooperatively induce interferon-beta, establishing host-virus detente

Tumor necrosis factor (TNF)-related cytokines regulate cell death and survi val and provide strong selective pressures for viruses, such as cytomegalov irus (CMV), to evolve counterstrategies in order to persist in immune-compe tent hosts. Signaling by the lymphotoxin (LT)-beta receptor or TNF receptor -1, but not Fas or TRAIL receptors, inhibits the cytopathicity and replicat ion of human CMV by a nonapoptotic, reversible process that requires nuclea r factor kappaB (NF-kappaB)dependent induction of interferon-beta (IFN-beta ). Efficient induction of IFN-beta requires virus infection and LT signalin g, demonstrating the need for both host and viral factors in the curtailmen t of viral replication without cellular elimination. LT alpha -deficient mi ce and LT betaR-Fc transgenic mice were profoundly susceptible to murine CM V infection. Together, these results reveal an essential and conserved role for LTs in establishing host defense to CMV.