MODIFICATION OF TRANSLATIONAL CONTROL ELEMENTS AS A NEW APPROACH TO DESIGN OF ATTENUATED PICORNAVIRUS STRAINS

The translation machineries of different host cells may exhibit varyin g requirements for a specific structure of cis-acting control elements in the viral RNA templates. Thus, the appropriately spaced oligopyrim idine/AUG tandem (OAT), a conserved control element in the 5' noncodin g region of the picomavirus genomes, is dispensable for the growth of Theiler's murine encephalomyelitis virus (TMEV) in BHK-21 cells, but i s essential for the neurovirulence of this virus. Also, the replacemen t of the cryptic (non-initiator) AUG moiety of the wild-type polioviru s 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 rat ional way to construct novel attenuated viral strains by elimination o r severe modification of host-specific regulatory regions in their gen omes. The relevant genetic rearrangements may be so extensive that the probability of reversion to the virulent phenotype should be negligib le. The feasibility of engineering of highly attenuated and geneticall y stable TMEV and poliovirus variants is illustrated.