Human Cytomegalovirus-Induced Autophagy Prevents Necroptosis of Infected Monocytes.

Key to the viral dissemination strategy of human cytomegalovirus (HCMV) is the induction of monocyte survival, where monocytes are normally short-lived cells. Autophagy is a cellular process that preserves cellular homeostasis and promotes cellular survival during times of stress. We found that HCMV rapidly induced autophagy within infected monocytes. The early induction of autophagy during HCMV infection was distinctly required for the survival of HCMV-infected monocytes, as repression of autophagosome formation led to cellular death of infected cells but had no effect on the viability of uninfected monocytes. The inhibition of caspases was insufficient to rescue cell viability of autophagy-repressed infected monocytes, suggesting that autophagy was not protecting cells from apoptosis. Accordingly, we found that HCMV blocked the activation of caspase 8, which was maintained in the presence of autophagy inhibitors. Necroptosis is an alternative form of cell death triggered when apoptosis is impeded and is dependent on RIPK3 phosphorylation of MLKL. Although we found that HCMV activated RIP3K upon infection, MLKL was not activated. However, inhibition of autophagy removed the block in RIPK3 phosphorylation of MLKL, suggesting that autophagy was protecting infected monocytes from undergoing necroptosis. Indeed, survival of autophagy-inhibited HCMV-infected monocytes was rescued when MLKL and RIPK3 were suppressed. Taken together, these data indicate that HCMV induces autophagy to prevent necroptotic cell death in order to ensure the survival of infected monocytes and thus facilitate viral dissemination within the host.