Inbred strains of mice and wild mouse species differ in their susceptibility to retroviruses and retrovirus-induced diseases. These differences have been attributed to various mouse chromosomal genes, and these genes include endogenous retroviral sequences, mouse cellular genes which facilitate or restrict virus replication, and proto-oncogenes disrupted by viral insertion. We have been using various approaches to identify and chromosomally map mouse genes involved in this resistance, and to characterize the viral targets of resistance. In one series of experiments, we used site-specific mutagenesis to alter the viral sequences in the CA gene of viral gag which had been previously identified as the target of the product of the cellular resistance gene, Fv1. We found that alteration of a single amino acid will change the resistance phenotype, and we produced at least one virus with a novel resistance pattern by amino acid substitution at this site. In other experiments, we have been collaborating with other groups to characterize chromosomal sites which represent common sites of proviral integration in tumor tissue. We found that Moloney virus infected mice transgenic for the c-myc gene under the control of the MMTV long terminal repeat contained a high proportion of tumors in which integrations produced altered expression of the mouse homolog of Notch1, a gene which controls cell fate determination in several tissues. This suggests a collaboration between myc and Notch1 in the disease process. We also examined common integration sites in erythroleukemias induced by Friend ecotropic virus and mapped one such site to distal Chr 9. Fine mapping showed that this site is at or very near the resistance gene Fv2. This integration is being used to further characterize this region and identify expressed genes which may represent candidates for Fv2.
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