The Theiler's murine encephalomyelitis viruses (TMEV) are ideally suited for molecular pathogenesis studies in animals. First the TMEV, as picornaviruses, are small, nonenveloped viruses which store all of their genetic information on one piece of single- strand, message-sense RNA- Second, these naturally occurring enteric pathogens of mice can be divided into two neurovirulence groups. Not only do the two groups produce different central nervous system diseases in mice, they also can be distinguished by a number of other phenotypic markers. Recently, the complete genomes of BeAn (less virulent group) and GDVII (highly virulent group) viruses were molecularly cloned in plasmid vectors and the complete nucleotide sequences determined in my laboratory. We also constructed a three-dimensional model of the coat proteins of BeAn virus on the atomic coordinates of Mengovirus, providing valuable information about structural features of the Theiler's virion prior to crystallographic analysis. A relative conservation of surface residues was observed in the viral receptor attachment site (pit) between Mengovirus and BeAn virus. In this proposal, we intend to test whether amino acids in the putative viral receptor attachment site (pit) are involved in binding of the TMEV to the cell receptor. This will be accomplished by making oligonucleotide directed mutations in selected amino acids of the a surface residues that comprise the viral receptor attachment site (Pit). In addition, we will determine if deletion of the two major VP1 loops will result in a viable TMEV that is susceptible to the Sterling Winthrop Co. WIN compounds. Two WIN compounds are effective antiviral agents against the human enteroviruses and rhinoviruses. A viable TMEV deletion mutant susceptible to the WIN agents would permit treatment of mice with CNS virus persistence. Being able to eradicate CNS virus persistence would be useful for studying immune effector mechanisms of TMEV-induced demyelination
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