Figure 7. Proposed mechanism of action of RT3D + RT combination therapy.

The PKR recognizes and binds to double-stranded RNA molecules resulting in its auto-phosphorylation and the subsequent downstream phosphorylation of eIF2α. The phosphorylation of eIF2α switches off the host cell's translational machinery preventing viral protein translation A. RT3D prevents the phosphorylation of PKR leaving eIF2α in an un-phosphorylated state and the host cell's translational machinery intact B. RT combined with up-regulates CUG2 resulting in the activation of Ras and the downstream protein p38. The activation of this pathway switches off the PKR defence mechanism, allowing viral protein translation and increasing viral replication C. The increase in viral replication ultimately results in cell death via mitochondrial apoptotic signalling D.