Persistent infection of adult mink with the Aleutian mink disease parvovirus (ADV)leads to disturbances of immune regulation, including hypergammaglobulinemia, plasmacytosis, immune complex disease, interstitial and glomerulonephritis. Infection at the cellular level is noncytopathic and restricted. In contrast, infections in cell culture and in newborn mink are cytopathic and fully permissive. Studies in cell culture indicate that ADV induces programmed cell death (apoptosis) and is in fact dependent upon apoptosis for complete viral replication. We determined that the main ADV nonstrucutral protein (NS1) is cleaved twice by caspases and that mutagenesis of the caspase recognition sites interfers with virus replication. Furthermore, caspase cleavage is required for nuclear localization of NS1 and may be needed for NS1 to carry out fucntions in DNA replication and gene expression. This is the first demonstration that direct interactions between apoptotic effectors and viral proteins can facilitate replication of DNA viruses. Suppression of such interactions may enable persistence of ADV. Virus is neutralized in vitro, but not in vivo, and infectious immune complexes occur. Capsid based vaccines are uniformly ineffective and induce acclerated disease. Major goals are: to correlate specific genomic sequences to functional correlates, such as determinants of host-range, persitence and pathogenicity; and to study the actual structure of the ADV virion. Understanding of the structure at high resolution will enable us to (a) relate epitopes and pathogenicity determinants to discreet coordinates on the viral particle, (b) relate structural features to the unique biology of ADV in vivo. By studying chimeric and site-directed mutant ADVs, we found that control of in vivo host range and persistent infections can be separated from expression of pathogenicity, although all are governed by amino acids in the capsid. Studies using antibodies against short capsid protein peptides indicate that a single epitope is involved with virus neutralization, immune complex formation, and ADE. This finding may explain the failure of capsid based vaccines.
