Sindbis virus suppresses Akt/mTOR signaling late during infection and induces mTOR independent antiviral response in HEK293T cells (67.12)

Abstract

Abstract Sindbis (SIN), an alphavirus has potent oncolytic properties and mTOR specific inhibitors are tested in combination with oncolytic viruses. Our aim was to study the effect of SIN replication on PI3K/Akt/mTOR signaling and its possible implications on innate antiviral response. In the presence and absence of PI3K/ mTOR inhibitors, HEK 293T cells were infected with SIN and UV-SIN. Replication of SIN was unaltered by the presence of inhibitors Ly294002, rapamycin and torin1 and rather suppressed phosphorylation of Akt, mTOR, S6 and 4E-BP1 late during infection. Currently, we are focusing on the effect of SIN infection on Akt phosphorylation in response to a subsequent growth stimulus in serum starved cells. PI3K/Akt pathway is required for IRF3 phosphorylation and expression of antiviral genes, which led us to study the regulation of these factors during SIN infection in the presence of inhibitors. Increased IRF3 phosphorylation and higher mRNA levels for ISG56 and IP-10 were seen with high intracellular viral RNA late during infection. Rapamycin and torin1 upregulated these antiviral responses, whereas prolonged Ly treatment partially blocked them. These results suggest that activation of IRF3 by SIN may be independent of mTOR, but partially dependent on PI3K/Akt. The potent inhibition of Akt/mTOR signaling by SIN may find applications in counteracting cellular drug resistance to kinase inhibitors and foster studies on engineered SIN genotypes in combination therapies.