Restoring immune defenses via lymphotoxin signaling: lessons from cytomegalovirus

Although primary infection with human cytomegalovirus (HCMV), a beta-herpesvirus, is widespread and acquired early in life, it rarely causes disease in immune-competent individuals. However, in immune-compromised patients HCMV infection or reactivation invariably leads to serious disease, the effective treatment of which remains a difficult clinical problem. Current antiviral therapy is limited not only by toxicity but also by the continual emergence of drugresistant viruses. The limitations of these current therapeutics provides a strong impetus to develop novel approaches that will enhance the host's immune responsiveness while at the same time effectively controlling virus replication. Type I interferon (IFN) plays a critical role in initiating innate antiviral defenses and promoting adaptive responses and lymphotoxin (LT)-alphabeta has recently been identified as an essential effector cytokine regulating the induction of type I IFN during CMV infection. In particular, CMV infection of immune-compromised mice has revealed the immunotherapeutic potential of the lymphotoxin-beta receptor (LTbetaR) signaling pathway to restore immune function and provide protection from CMV mortality. In this review, we discuss the potential benefits and risks associated with LTbetaR-directed immunotherapy for CMV disease and other persistent viral infections.