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

Translation initiation of the picornavirus genome is regulated by an intern al ribosome entry site (IRES). The IRES of a neurovirulent picornavirus, th e GDVII strain of Theiler's murine encephalomyelitis virus, requires polypy rimidine tract-binding protein (PTB) for its function. Although neural cell s are deficient in PTB, they express a neural-specific homologue of PTB (nP TB). We now show that nPTB and PTB bind similarly to multiple sites in the GDVII IRES, rendering it competent for efficient translation initiation. Mu tation of a PTB or nPTB site results in a more prominent decrease in nPTB t han PTB binding, a decrease in activity of nPTB compared with PTB in promot ing translation initiation, and attenuation of the neurovirulence of the vi rus without a marked effect on virus growth in non-neural cells. The additi on of a second-site mutation in the mutant IRES generates a new PTB (nPTB) binding site, and restores nPTB binding, translation initiation and neurovi rulence. We conclude that the tissue-specific expression and differential R NA-binding properties of PTB and nPTB are important determinants of cell-sp ecific translational control and viral neurovirulence.