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polio IRES mutant - JOURNAL OF VIROLOGY Jan 2003 p 115122...

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J OURNAL OF V IROLOGY , Jan. 2003, p. 115–122 Vol. 77, No. 1 0022-538X/03/$08.00 0 DOI: 10.1128/JVI.77.1.115–122.2003 Copyright © 2003, American Society for Microbiology. All Rights Reserved. Impaired Binding of Standard Initiation Factors Mediates Poliovirus Translation Attenuation Kerstin Ochs,† Amandus Zeller, Lanja Saleh, Gergis Bassili, Yutong Song, Anja Sonntag, and Michael Niepmann* Institute of Biochemistry, Faculty of Medicine, Justus-Liebig-Universita ¨t Giessen, 35392 Giessen, Germany Received 22 July 2002/Accepted 26 September 2002 In the oral poliovirus vaccine, three attenuated virus strains generated by Albert Sabin are used. However, insufficient genetic stability of these strains causes major problems in poliovirus eradication. In infected cells, translation of the plus-strand poliovirus RNA genome is directed by the internal ribosome entry site (IRES), a cis -acting RNA element that facilitates the cap-independent binding of ribosomes to an internal site of the viral RNA. In each Sabin vaccine strain, a single point mutation in the IRES secondary-structure domain V is a major determinant of neurovirulence attenuation. Here we report how these decisive mutations in the IRES confer a reduction in poliovirus translation efficiency. These single-nucleotide exchanges impair the interaction of the standard translation initiation factor eIF4G with the IRES domain V. Moreover, binding of eIF4B and the polypyrimidine tract-binding protein and the association of ribosomes with the viral RNA are affected by these mutations. However, the negative effects of the IRES mutations are completely relieved by addition of purified eIF4F. This indicates that eIF4G is the crucial factor that initially binds to the poliovirus IRES and recruits the IRES to the other components of the translational apparatus, while impaired binding of eIF4G plays a key role in attenuation of poliovirus neurovirulence. Three attenuated poliovirus live-vaccine strains that had been obtained after serial cell culture passages (40) are suc- cessfully used in the oral poliovirus vaccine (OPV) for fighting poliovirus. Nevertheless, the exclusive use of these OPV strains for globally eradicating the virus is hampered by its insufficient genetic stability (18), which causes major challenges for public health organizations (27). In many cases, the genetic instability of the OPV strains resides in the 5 untranslated region (5 - UTR) of the poliovirus plus-strand genomic RNA (4, 43). Here we report how these decisive mutations in the viral 5 - UTR confer a reduction in poliovirus translation efficiency. After infection of a susceptible cell, the plus-strand poliovi- rus RNA is directly used for translation of viral gene products. Initiation of translation is mediated by the internal ribosome entry site (IRES), a cis -acting element in the viral 5 -UTR.
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