The E2-E166K substitution restores Chikungunya virus growth in OAS3 expressing cells by acting on viral entry

Human 2',5'-oligoadenylate synthetase 3 (OAS3) exerts antiviral effect against alphaviruses including Chikungunya virus (CHIKV) by inhibiting viral RNA accumulation. Here, we identified a CHIKV variant exhibiting a remarkable resistance to the antiviral action of OAS3 in human epithelial HeLa cells. Using a molecular clone of CHIKV with Renilla luciferase inserted as a reporter gene in the non-structural region, we demonstrated that a single glutamine-to-lysine amino acid change at position 166 of the envelope E2 glycoprotein restores CHIKV replication in OAS3 expressing HeLa cells. Viral entry assays showed that CHIKV with a lysine at position E2-166 was more efficient at entering the replicative pathway. The E2-E166K substitution promotes a greater efficiency of CHIKV replication in human myoblasts leading to severe apoptosis through a more robust activation of the PKR pathway. These observations provide a new insight into the role of E2 into the pathogenicity of CHIKV in human cells.