Alphaviruses can infect a broad range of vertebrate hosts, including birds, horses, primates, and humans, in which infection can lead to rash, fever, encephalitis, and arthralgia or arthritis. They are most often transmitted by mosquitoes in which they establish persistent, asymptomatic infections. Currently, there are no vaccines or antiviral therapies for any alphavirus. Several Old World alphaviruses, including Semliki Forest virus, Ross River virus and chikungunya virus, activate or hyperactivate the phosphatidylinositol-3-kinase (PI3K)-AKT pathway in vertebrate cells, potentially influencing many cellular processes, including survival, proliferation, metabolism and autophagy. Inhibition of PI3K or AKT inhibits replication of several alphaviruses either in vitro or in vivo, indicating the importance for viral replication. In this review, we discuss what is known about the mechanism(s) of activation of the pathway during infection and describe those effects of PI3K-AKT activation which could be of advantage to the alphaviruses. Such knowledge may be useful for the identification and development of therapies.Cells 2020, 9, 970 2 of 12 complex mTORC1. AKT signalling leads to the activation of mTORC1, which promotes cell growth by inducing lipid biogenesis through activation of the transcription factors SREBP1 and PPARγ and by promoting protein synthesis by activating the S6 kinase (S6K) and by inactivating the translational inhibitor 4E-BP1. mTORC1 also inhibits autophagy by blocking ULK1 [6]. The serine/threonine kinase glycogen synthase kinase 3 (GSK3) is another multifunctional target of AKT. Through phosphorylation, active GSK3 inhibits most of its substrates. Upon phosphorylation by AKT, GSK3 itself is inhibited and thereby the downstream targets are positively regulated. These targets include the prosurvival BCL-2 family member MCL-1 and the transcription factor c-Myc, which is required for expression of many genes involved in proliferation. Other GSK3-targets, such as glycogen synthase, are involved in (regulation of) cellular metabolism [7]. The third multifunctional target of AKT are the forkhead box O (FoxO) transcription factors. Phosphorylation of FoxO transcription factors by AKT leads to acute translocation out of the nucleus. Thus, AKT signalling suppresses the expression of FoxO targets. These include targets involved in the induction of apoptosis, cell-cycle arrest, catabolic metabolism and growth inhibition. Thus, PI3K-AKT signalling via these multifunctional targets promotes cell survival, growth and proliferation and steers cellular metabolism towards anabolism.