IRES elements are 400-nucleotide-(nt)-long segments within the 5′NTR of picornavirus genomic RNAs that allow initiation of protein synthesis independently of a 5′ end ( 14, 27) (Fig. This region was subsequently identified as domain V of the internal ribosomal entry site (IRES) of PV (reviewed in reference 41). Studies of the attenuated PV vaccine strains of Sabin ( 32) have revealed that, remarkably, some of the attenuating mutations map to a specific region in the 5′ nontranslated region (5′NTR) of the viral genome ( 6, 16, 26). Neurological disease, culminating in flaccid paralysis, evolves with the progressive destruction of motor neurons by PV in the spinal cord anterior horn, a condition called poliomyelitis ( 4, 31). Poliovirus (PV), the prototype of the genus Enterovirus of the family Picornaviridae, has a markedly restricted tissue tropism that is limited to unidentified cells within the gastrointestinal tract and to motor neurons in the spinal cord and brainstem. Tissue tropism and pathogenic properties of a virus are determined largely by the cellular receptor(s) and an intracellular milieu suitable for viral proliferation. We report that two adjacent stem loop structures within the IRES cooperatively determine neuropathogenicity. We have dissected the PV and HRV2 IRES elements to determine those structures responsible for neurovirulence (or attenuation) of these chimeric viruses. We now show that attenuation of neurovirulence of PV/HRV2 chimeras is not confined to CD155 transgenic mice but is evident also after intraspinal inoculation into Cynomolgus monkeys. We reported previously that the exchange of the cognate internal ribosomal entry site (IRES) within the 5′ nontranslated region of PV with its counterpart from human rhinovirus type 2 (HRV2) can eliminate the neuropathogenic phenotype in a transgenic mouse model for poliomyelitis without diminishing the growth properties in HeLa cells. PV tropism is likely to be determined by cell-external components such as the PV receptor CD155, as well as cell-internal constraints such as the availability of a suitable microenvironment for virus propagation. In the human central nervous system, susceptibility to poliovirus (PV) infection is largely confined to a specific subpopulation of neuronal cells.
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