Cytomegalovirus Biology Viewed Through a Cell Death Suppression Lens

Cytomegaloviruses, species-specific members of the betaherpesviruses, encode an impressive array of immune evasion strategies committed to the manipulation of the host immune system enabling these viruses to remain for life in a stand-off with host innate and adaptive immune mechanisms. Even though they are species-restricted, cytomegaloviruses are distributed across a wide range of different mammalian species in which they cause systemic infection involving many different cell types. Regulated, or programmed cell death has a recognized potential to eliminate infected cells prior to completion of viral replication and release of progeny. Cell death also naturally terminates replication during the final stages of replication. Over the past two decades, the host defense potential of known programmed cell death pathways (apoptosis, necroptosis, and pyroptosis), as well as a novel mitochondrial serine protease pathway have been defined through studies of cytomegalovirus-encoded cell death suppressors. Such virus-encoded inhibitors prevent virus-induced, cytokine-induced, and stress-induced death of infected cells while also moderating inflammation. By evading cell death and consequent inflammation as well as innate and adaptive immune clearance, cytomegaloviruses represent successful pathogens that become a critical disease threat when the host immune system is compromised. This review will discuss cell death programs acquired for mammalian host defense against cytomegaloviruses and enumerate the range of modulatory strategies this type of virus employs to balance host defense in favor of lifelong persistence.