PKR Binds Enterovirus IRESs, Displaces Host Translation Factors, and Impairs Viral Translation to Enable Innate Antiviral Signaling

For RNA virus families except Picornaviridae, viral RNA sensing includes Toll-like receptors and/or RIG-I. Picornavirus RNAs, whose 5′ termini are shielded by a genome-linked protein, are predominately recognized by MDA5. This has important ramifications for adaptive immunity, as MDA5-specific patterns of type-I interferon (IFN) release are optimal for CD4(+)T cell T(H)1 polarization and CD8(+)T cell priming. We are exploiting this principle for cancer immunotherapy with recombinant poliovirus (PV), PVSRIPO, the type 1 (Sabin) PV vaccine containing a rhinovirus type 2 internal ribosomal entry site (IRES). Here we show that PVSRIPO-elicited MDA5 signaling is preceded by early sensing of the IRES by the double-stranded (ds)RNA-activated protein kinase (PKR). PKR binding to IRES stem-loop domains 5–6 led to dimerization and autoactivation, displaced host translation initiation factors, and suppressed viral protein synthesis. Early PKR-mediated antiviral responses tempered incipient viral translation and the activity of cytopathogenic viral proteinases, setting up accentuated MDA5 innate inflammation in response to PVSRIPO infection.