GENETIC ASPECTS OF VIRAL ONCOGENESIS IN WILD MOUSE SPECIES

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Abstract

The various wild mice and inbred strains differ from one another in their susceptibility to retroviruses and retrovirus-induced diseases. These differences are due to allelic differences in specific mouse chromosomal genes, and we have been engaged in an ongoing effort to identify and characterize the mouse genes involved in this resistance. This year, we continued to investigate the viral resistance gene, Fv1, which is responsible for partial resistance to all mouse-tropic MLVs. One allele of this gene, nr, controls resistance to all B-tropic viruses and some N-tropic viruses. We sequenced the viral capsid gene of AKR-L1, the target of Fv1-mediated resistance. We identified a single amino acid difference and used site specific mutagenesis to confirm this change to be responsible for the nr phenotype. This site is different from the site we previously determined to be responsible for relative resistance to N- and B-tropic viruses. We are also characterizing a serum factor found in most mice that inactivates leukemia viruses. We have shown that this factor does not inactivate viruses of the ecotropic and amphotropic host range groups, but that it strongly inactivates polytropic viruses and, less strongly, xenotropic viruses. We have determined that the presence of this factor is under single gene control and we used a genome scan to determine the map location of the responsible locus. We have identified two genes that map to this region as possible candidates for the serum factor. In other studies, we have identified a novel chromosomal site into which integrated viruses have been identified in tumor tissue indicating the presence of a novel gene involved in neoplastic transformation. Finally, we have also continued our efforts to characterize the resistance gene Rmcf, which is responsible for partial resistance to the polytropic class of MLVs. We have now cloned a chromosomally integrated copy of the viral envelope associated with Rmcf, and are now in the process of sequencing to determining whether this envelope is part of a complete retrovirus, or whether, like the comparable Fv-4 resistance gene, it represents a truncated provirus that is expressed from a cellular promoter.