Minute virus of mice (MVM) is a member of the autonomous subgroup of the parvoviruses, small single-stranded DNA-containing animal viruses which exhibit teratogenic and tumor-suppressive activity in vivo. We proposed to elucidate the mechanism behind the specific tissue-tropism exhibited by the agents during pathogenesis. The combined approaches of viral and somatic cell genetics are being used to analyse, at the molecular level, developmentally regulated host factors essential for MVM growth, and the viral components with which the host factors interact - the combination of which determines the virus strain-specific tissue tropism. We are characterizing the virus-host interactions of two strains of MVM which are reciprocally restricted for growth in T-lymphocytes and fibroblasts. Also being studied is the mechanism of establishment and maintenance of persistent infections in these restrictive interactions and the evolution during such infections of extended host range mutants of each strain. The genetic determinant specifying host range within differentiated cell types of the same host species is being mapped by the in vitro construction of recombinants between parental strains and host range mutants derived from them. Complementation experiments are being carried out to elucidate the mode of action of this viral locus. MVM-resistant cell mutants are being isolated from normally susceptible populations an characterized. Some of these appear to be defective in expression of developmentally regulated factors required for MVM replication and will provide host cells for the isolation of new variants and assays with which enrichment for cloned cellular helper genes may be achieved. These cell lines are being analysed by somatic cell fusion for complementation, in order to enumerate host genes required for virus replication but not cell growth, and to determine biochemically the point in the virus life cycle at which these factors act. These cells will be used to construct, by fusion, novel host cells with which we will attempt to select or create new virus variants which will infect and kill specific tumor cell types. With these we will explore directed oncolysis in the whole animal
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