The role of PI3K/Akt in human herpesvirus infection: From the bench to the bedside

- Human herpesvirus replication and latency proteins activate the PI3K/Akt pathway.
- PI3K/Akt is important for protein synthesis, transformation, and blocking apoptosis.
- Constitutive activation of PI3K is associated with severe herpesvirus infections.
- PI3K/Akt is activated in several EBV and KSHV associated malignancies.
- Drugs that block PI3K/Akt might be used to treat herpesvirus infections or cancers.

The phosphatidylinositol-3-kinase (PI3K)-Akt signaling pathway regulates several key cellular functions including protein synthesis, cell growth, glucose metabolism, and inflammation. Many viruses have evolved mechanisms to manipulate this signaling pathway to ensure successful virus replication. The human herpesviruses undergo both latent and lytic infection, but differ in cell tropism, growth kinetics, and disease manifestations. Herpesviruses express multiple proteins that target the PI3K/Akt cell signaling pathway during the course of their life cycle to facilitate viral infection, replication, latency, and reactivation. Rare human genetic disorders with mutations in either the catalytic or regulatory subunit of PI3K that result in constitutive activation of the protein predispose to severe herpesvirus infections as well as to virus-associated malignancies. Inhibiting the PI3K/Akt pathway or its downstream proteins using drugs already approved for other diseases can block herpesvirus lytic infection and may reduce malignancies associated with latent herpesvirus infections.