Distinct attenuation phenotypes caused by mutations in the translational starting window of Theiler's murine encephalomyelitis virus

Upon initiation of translation of picornavirus RNA, the ribosome is believe d to bind the internal ribosome entry site of the template and then to form a productive complex with a downstream RNA segment, the starting window, T he presence or absence of an AUG triplet within the starting window of the RNA of Theiler's murine encephalomyelitis virus (a picornavirus) is known t o modulate its neurovirulence. In this study, mutants of this virus in whic h the starting windows, lying upstream of the viral polyprotein reading fra me, had AUGs with different nonoptimal contexts were engineered. Upon intra cerebral inoculation of mice, the mutants proved to be partially attenuated , as judged by a significant increase in the dose causing paralysis in 50% of the animals (PD50). Mutants with similar PD(50)s might differ from one a nother by eliciting either a severe, fatal tetraplegy or only mild, recover able neurologic lesions. Some of the mutants triggered a chronic inflammato ry reaction in the white matter of the spinal cord in the absence of detect able viral RNA or antigen. Thus, point mutations changing the context of an AUG within the starting window outside the polyprotein reading frame may d ifferently affect the morbidity and mortality caused by a viral infection a nd may result in distinct attenuation phenotypes.