The autonomous parvoviruses are small, single-stranded DNA-containing viruses which can induce fetal demise and teratogenic effects during pregnancy and can interfere with both normal tissue turnover and the development of neoplastic disease in their adult host. The proposed research is aimed at understanding the basis of parvoviral tissue-tropism and the mechanisms by which the viruses initiate either productive or latent life cycles in their host cells. The viral non-structural proteins of the murine virus will be further studied to discover their individual roles in pathogenesis at the level of the cell and of the whole animal. The genes will be functionally separated by mutagenesis, recovered as virus and used to infect target cells, in order to assess their effects on cellular physiology and the viral life cycle, and to explore intra-viral genetic control circuits. Trans-encapsidation experiments will be performed with allotropic strains of the murine virus in order to confirm that host cell specificity is controlled by a small region of coat protein located on the virion surface. Large-scale production of virions will be undertaken to provide material for structure determination by x-ray crystallography. Amino acid residues involved in the putative host range ligand and in the antibody neutralization properties of the virion will be mapped in three dimensions. An anti-idiotype strategy for identifying the intra-cellular receptor for the host range determinant will be pursued, and the step in the viral life cycle which this interaction catalyses will be determined by following the fate of parental virions and their associated genomes. Finally, the long-term fate of viral genomes in non-productive virus:host cell interactions will be studied for both human and murine parvoviruses. These virus:host interactions will be examined to determine the mechanism by which the viral genome persists in its host cell.
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