Cell-specific proteins regulate viral RNA translation and virus-induced disease

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Abstract
Translation initiation of the picornavirus genome is regulated by an internal ribosome entry site (IRES). The IRES of a neurovirulent picornavirus, the GDVII strain of Theiler's murine encephalomyelitis virus, requires polypyrimidine tract‐binding protein (PTB) for its function. Although neural cells are deficient in PTB, they express a neural‐specific homologue of PTB (nPTB). We now show that nPTB and PTB bind similarly to multiple sites in the GDVII IRES, rendering it competent for efficient translation initiation. Mutation of a PTB or nPTB site results in a more prominent decrease in nPTB than PTB binding, a decrease in activity of nPTB compared with PTB in promoting translation initiation, and attenuation of the neurovirulence of the virus without a marked effect on virus growth in non‐neural cells. The addition of a second‐site mutation in the mutant IRES generates a new PTB (nPTB) binding site, and restores nPTB binding, translation initiation and neurovirulence. We conclude that the tissue‐specific expression and differential RNA‐binding properties of PTB and nPTB are important determinants of cell‐specific translational control and viral neurovirulence.