Inhibition of Akt kinase activity suppresses entry and replication of influenza virus

Abstract

The possibility of the pandemic spread of influenza viruses highlights the need for an effective cure for this life-threatening disease. Influenza A virus, belonging to a family of orthomyxoviruses, is a negative-strand RNA virus which encodes 11 viral proteins. A numbers of intracellular signaling pathways in the host cells interact with influenza the viral proteins, which affect various stages of viral infection and replication. In this study, we investigated how inhibition of Akt kinase activity impacts on influenza virus infection by using "Akt-in", a peptide Akt inhibitor. In PR8 influenza-infected A549 cells, Akt interacted with the NS1 (Non structural protein 1), and hence increased phosphorylation of Akt kinase activity and NS1. Treatment of cells with either "TCL1- or TCL1b-based Akt-in" efficiently suppressed Akt kinase activity while decreasing the levels of phosphorylated NS1; this, in turn, inhibited viral replication in a dose- and time-dependent manner. The inhibitory effect on viral replication appears to not be due to inhibition of the production of inflammatory cytokines, including IL-6 and IL-8, in the host cells. Inhibition of Akt kinase activity in the host cells inhibited the efficiency of viral entry, which is associated with decreased levels of phosphorylated glycogen synthase kinase 3, a substrate of Akt. Thus inhibition of Akt kinase activity in host cells may have therapeutic advantages for influenza virus infection by inhibiting viral entry and replication.

Targeting Metabolic Reprogramming by Influenza Infection for Therapeutic Intervention

“…However, in spite of in vitro antiviral activity in this study the mTOR inhibitor everolimus had no effect in vivo (Murray et al, 2012). Hirata and coworkers found using a peptide inhibitor of Akt kinase they could suppress entry and replication of the mouse adapted PR8 virus into the A549 cell line, in contrast to BEZ235 which we found had no effect on entry and genome replication in human primary epithelial cells (Hirata et al, 2014) (Fig. 5C).…”

“…Likewise we see that the transient increase in cMyc expression induced by influenza infection is ablated by BEZ235 treatment in both NHBE donors (Figure 5B). Akt and PI3K inhibitors can block viral entry in transformed cell lines (Hirata et al, 2014; Shin et al, 2007). Preventing viral entry could explain reduced viral titer, c-Myc expression, and altered PI3k/mTOR activity.…”

Broad-Spectrum Inhibition of Respiratory Virus Infection by MicroRNA Mimics Targeting p38 MAPK Signaling

“…The RPPA study identified additional proteins that may be targeted by these miRNAs, such as miR-744 targeting of Akt or miR-124a and miR-24 suppression of GSK-3β, as both of these factors were previously shown to be important for influenza virus entry 56, 57. Other previously identified roles of these miRNAs in viral infection include miR-24 suppression of Kruppel-like factor 6, which is induced by RSV infection to induce cell-cycle arrest, 14 as well as the suppression of furin by miR-24, which is required for influenza virus activation, 58 and miR-124a attenuation of Japanese encephalitis virus (JEV) via targeting dynamin2, which is required for efficient JEV replication 59 .…”

Ethanolic Extract of Melia Fructus Has Anti-influenza A Virus Activity by Affecting Viral Entry and Viral RNA Polymerase

“…We found EMF inhibited HA and NA activity ( Figure 3 ), implying that the inhibition of virus infection by EMF results from blocking the HA-sialic acid receptor interaction and NA activity in the early stages of infection. The PI3K/AKT signaling pathway regulates viral entry, and the inhibition of AKT kinase activity suppresses viral entry and replication (Ehrhardt et al, 2006; Hirata et al, 2014). We found that EMF treatment decreased AKT phosphorylation ( Figure 6 ).…”