Genetic Aspects Of Viral Oncogenesis In Wild Mouse Speci

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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 several mouse genes involved in this resistance: - We have continued our analysis of a serum lipoprotein factor found in most mice that inactivates leukemia viruses. We have demonstrated that production of this factor is controlled by a single gene. We have mapped this gene to a position on mouse chromosome 10 and evaluated a candidate gene, Apof (apolipoprotein F). These experiments showed that this serum factor is controlled by another closely linked gene, and we are in the process of evaluating a second candidate from this region. We are also generating congenics to determine how presence or absence of this factor affects disease progression. - We have continued our efforts to characterize the resistance gene Rmcf, which is responsible for partial resistance to the highly pathogenic polytropic class of leukemia viruses. We have cloned a chromosomally integrated copy of the viral envelope linked to the Rmcf locus, and shown that its expression is associated with virus resistance. This suggests that Rmcf resistance may be mediated through an interference mechanism. We have also identified a similar resistance phenotype in the wild mouse M. castaneus (termed Rmcf2) and we have identified an associated proviral sequence that is now being cloned and characterized. - We are examining the wild mouse species, M. spretus, M. musculus and M. spicilegus for susceptibility to virus infection and for novel leukemia viruses. From M. spicilegus we have isolated a novel virus variant that induces cytopathic changes in specific mouse cells. Sequence analysis has shown that this variant has a single amino acid substitution in one of the 3 amino acids that form the receptor binding site. This virus causes cytopathic effects in a cell line with a variant receptor gene and we are using this virus-receptor combination to examine viral entry. In other experiments we determined that inoculation of M. spretus mice with a laboratory mouse virus resulted in the generation of recombinant virus. We showed that the recombinant viruses had acquired substantial substitutions in the envelope glycoprotein gene that resulted in altered host range properties. We also showed that the endogenous proviruses found in this wild mouse are highly homologous suggesting they were recently acquired. - We have completed a study with Dr. R. Carp in which we examined the senescence prone and resistant SAM mouse strains for endogenous virus expression and found that the strains with accelerated aging share a specific provirus, Akv1, inherited from the AKR mouse progenitor of these strains. We found this virus to be highly expressed in thymus, spleen and brain of strains with accelerating aging. - Finally, we have developed several resources useful for mouse genomic analysis and mapping. We used these resources in a collaborative project with Dr. E. Rassart to identify a novel site of preferred integration for an oncogenic virus.