Modification of translational control elements as a new approach to design of attenuated picornavirus strains.
The translation machineries of different host cells may exhibit varying requirements for a specific structure of cis-acting control elements in the viral RNA templates. Thus, the appropriately spaced oligopyrimidine/AUG tandem (OAT), a conserved control element in the 5' noncoding region of the picornavirus genomes, is dispensable for the growth of Theiler's murine encephalomyelitis virus (TMEV) in BHK-21 cells, but is essential for the neurovirulence of this virus. Also, the replacement of the cryptic (non-initiator) AUG moiety of the wild-type poliovirus OAT by the initiator AUG affects the viral reproduction in cultured cells only slightly, whereas neurovirulence of the relevant mutants is dramatically suppressed. These observations allow us to propose a rational way to construct novel attenuated viral strains by elimination or severe modification of host-specific regulatory regions in their genomes. The relevant genetic rearrangements may be so extensive that the probability of reversion to the virulent phenotype should be negligible. The feasibility of engineering of highly attenuated and genetically stable TMEV and poliovirus variants is illustrated.
Agol
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M.P. Chumakov Institute of Poliomyelitis & Viral Encephalitides, Russian Academy of Medical Sciences, Moscow Region, Russia.
Pilipenko
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EV
Slobodskaya
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OR
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017124:Conserved Sequence; D006224:Cricetinae; D015195:Drug Design; D005818:Genetic Engineering / Q000379:methods; D016679:Genome, Viral; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009843:Oligoribonucleotides; D010849:Picornaviridae / Q000235:genetics* / Q000276:immunology*; D017955:Poliovirus / Q000276:immunology; D014176:Protein Biosynthesis; D012367:RNA, Viral / Q000737:chemistry / Q000378:metabolism*; D012091:Repetitive Sequences, Nucleic Acid; D017945:Theilovirus / Q000276:immunology; D014613:Vaccines, Attenuated; D014614:Vaccines, Synthetic; D014765:Viral Vaccines
D009843:Oligoribonucleotides; D012367:RNA, Viral; D014613:Vaccines, Attenuated; D014614:Vaccines, Synthetic; D014765:Viral Vaccines