The TORrid affairs of viruses: effects of mammalian DNA viruses on the PI3K–Akt–mTOR signalling pathway

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Abstract
The successful replication of mammalian DNA viruses requires viral adaptation of the host cell to establish an environment that can accommodate the increased demands for nutrients, energy and macromolecular synthesis that accompany viral infection. Therefore, the DNA viruses must gain control of key cellular signalling pathways that affect broad aspects of cellular macromolecular synthesis, metabolism, growth and survival, such as the phosphatidylinositol 3′-kinase–Akt–mammalian target of rapamycin (PI3K–Akt–mTOR) pathway. However, a viral mechanism for activating this pathway is not enough; to maintain control of this pathway, viruses must also overcome the many controls that cells use to inhibit this pathway when cellular stress responses are activated during viral infection. This Review discusses the normal activation and control of the PI3K–Akt–mTOR pathway, and why the activation and control of this pathway is important to mammalian DNA viruses. The authors also outline how the PI3K–Akt–mTOR pathway can be inhibited by signalling that is induced by the stress that is imposed on the cell by the viral lytic infection, for example, by the depletion of nutrients, energy, amino acids or oxygen. The range of mechanisms that mammalian DNA viruses use to activate the PI3K–Akt–mTOR pathway are discussed, as well as the multiple mechanisms that these viruses have evolved to circumvent the inhibitory stress signalling that would normally inhibit this pathway. This Review ends with a discussion of remaining questions about the viral control of the PI3K–Akt–mTOR pathway and how the manipulation of the pathway, and its downstream effectors, may contribute to viral pathogenesis.