Akt Inhibitor Akt-IV Blocks Virus Replication through an Akt-Independent Mechanism

Abstract

Many viruses activate the phosphatidylinositol 3-kinase (PI3k)/Akt intracellular signaling pathway to promote viral replication. We have analyzed whether a rapidly replicating rhabdovirus, vesicular stomatitis virus (VSV), requires the PI3k/Akt signaling pathway for its replication. Through the use of chemical inhibitors of PI3k and Akt, we show that VSV replication and cytopathic effects do not require activation of these kinases. Inhibitors that block the activating phosphorylations of Akt at threonine 308 (Thr308) and serine 473 (Ser473) did not inhibit VSV protein expression or the induction of the cytopathic effects of VSV. One compound, Akt inhibitor Akt-IV, inhibited the replication of VSV, respiratory syncytial virus, and vaccinia virus but increased the phosphorylation of Akt at positions Thr308 and Ser473 and did not inhibit Akt kinase activity in vitro. Together, our data suggest that the PI3k/Akt pathway is of limited relevance to the replication of VSV but that Akt inhibitor Akt-IV is a novel broad-spectrum antiviral compound with a mechanism differing from that of its previously reported effect on the PI3k/Akt pathway. Identification of other targets for this compound may define a new approach for blocking virus replication.

The PI3K/Akt Pathway Contributes to Arenavirus Budding

“…1B). The inability of Akt-IV to inhibit Akt phosphorylation was unexpected based on its published properties (38) but was consistent with a recent report showing that Akt-IV blocked VSV multiplication without affecting Akt phosphorylation (11). Akt-VIII has been shown to be a direct inhibitor of the kinase activity of Akt in several cell systems (2) and to have antiviral activity (1).…”

Dominant Inhibition of Akt/Protein Kinase B Signaling by the Matrix Protein of a Negative-Strand RNA Virus

“…This finding is in agreement with previous observations that VSV replication induces the dephosphorylation of 4EB-P1 (21) and downstream effectors of Akt (42) and that VSV replication is not dependent on an active PI3k/Akt signaling pathway (24). This runs counter to what has been seen for other viruses and even other negative-strand RNA viruses, such as influenza A virus and RSV, which are known to activate Akt (26,41,60).…”

A Phosphoinositide 3-Kinase (PI3K)-serum- and glucocorticoid-inducible Kinase 1 (SGK1) Pathway Promotes Kv7.1 Channel Surface Expression by Inhibiting Nedd4-2 Protein

“…We found that pharmacological inhibition of SGK1 in polarized MDCK cells resulted in disappearance of Kv7.1 channels from the surface membrane and intracellular accumulation of the channel. We observed similar effects by using Akt inhibitor IV but only at concentrations where it can also suppress SGK1 (48), suggesting that the observed effect could be due to inhibition of SGK1. In support Presented is a summary of three individual two-electrode voltage clamp experiments (n Ն 6 in each) in oocytes expressing Kv7.1 alone (normalized to 100) or in combination with Nedd4-2/Nedd4-2-CS and/or SGK/SGK KA, where Nedd4-2-CS and SGK KA are catalytically inactive versions of the respective enzymes.…”