Pim1 Impacts Enterovirus A71 Replication and Represents a Potential Target in Antiviral Therapy

Enterovirus A71 (EV-A71) infection causes hand-foot-and-mouth disease (HFMD) and fatal neurological diseases, and there are no effective treatments. Host factors play key roles in establishing viral infection and determining the disease progression and outcome of antiviral therapies. In this study, we found that the expression of Pim1 was significantly upregulated in EV-A71 infection. Ectopic expression or silencing of Pim1 promoted or inhibited EV-A71 replication through two distinct mechanisms. Pim1 enhanced viral IRES activity by increasing viral 2A protease-mediated eIF4G cleavage and blocked AUF1, a suppressor of IRES, translocation from the nucleus to cytosol. More importantly, we discovered that Pim1 inhibitors (SGI-1776, AZD-1208, and CX-6258) reduced EV-A71 reproduction. Particularly, CX-6258 remarkably reduced EV-A71 reproduction more than 1,000 times, providing a potential therapeutic agent for EV-A71 treatment.