A few nucleotide changes have a significant effect on the neurovirulent potential of the poliovirus genome. The most significant site, for Type 3, is located in a n untranslated region of the viral genome and affects viral translation. The recent description of a successful in vitro translation system from HeLa cells using added poliovirus RNA has offered a potential method to investigate and further define the role of the attenuating genome changes by defining and comparing the differences between wild type and Sabin attenuated genomes. Use of protein synthesis inhibitors provided evidence for a novel feedback regulatory mechanism linking poliovirus RNA synthesis to the level of ribosomal activity. Preliminary evidence linking the 5' untranslated region of the poliovirus genome associated with attenuation to this regulatory mechanismsuggests that attenuation reflects an alteration in this viral regulatory mechanism. Current research further defines the response in vivo and the development of an in vitro coupled polymerase/translation assay capable of reproducing events observed in vivo. The PI is responsible for the review of polio virus vaccine PLA and IND documents. A significant advance in our understanding of the molecular mechanisms for neuroattentuation of poliovirus vaccines would be served by the study of how a limited number of nucleotide changes at discrete positions in the poliovirus genome result in attenuation of the neurovirulent phenotype. Such knowledge can be used to produce improved, stabile attenuated viral strains, with reduced rates of reversion, resulting in fewer cases of vaccine related poliomyelitis. Furthermore, our studies can lead to molecularly based neurovirulence testing to predict the safety of new poliovirus vaccine strains, and to a fundamental understanding of how viruses employ regulatory mechanisms of cellular processes to promote viral replication.
