GENETIC ASPECTS OF VIRAL ONCOGENESIS IN WILD MOUSE SPECIES

各种野生小鼠和近交系在对逆转录病毒和逆转录病毒引起的疾病的易感性方面彼此不同。这些差异是由于特定小鼠染色体基因的等位基因差异，我们一直致力于识别和表征参与这种抗性的小鼠基因。今年，我们继续研究病毒抗性基因Fv1，该基因对所有嗜鼠型mlv具有部分抗性。该基因的一个等位基因nr控制对所有嗜b型病毒和一些嗜n型病毒的抗性。我们对fv1介导的耐药靶点AKR-L1的病毒衣壳基因进行了测序。我们发现了一个单一的氨基酸差异，并使用位点特异性诱变来证实这种变化是nr表型的原因。这个位点不同于我们先前确定的对嗜N型和嗜b型病毒具有相对抗性的位点。我们还描述了在大多数小鼠中发现的使白血病病毒失活的血清因子。我们已经证明，该因子不能灭活生态嗜性和两性嗜性宿主群的病毒，但能强烈灭活多嗜性病毒，而对异嗜性病毒的灭活作用较弱。我们已经确定这个因素的存在是在单基因控制下，我们使用基因组扫描来确定负责位点的地图位置。我们已经确定了两个基因映射到这个区域作为可能的候选血清因子。在其他研究中，我们发现了一个新的染色体位点，在肿瘤组织中发现了整合病毒，表明存在一种参与肿瘤转化的新基因。最后，我们还继续努力表征抗性基因Rmcf，该基因负责对多嗜性mlv类的部分抗性。我们现在已经克隆了一个与Rmcf相关的病毒包膜的染色体整合拷贝，现在正在进行测序，以确定该包膜是完整逆转录病毒的一部分，还是像类似的Fv-4抗性基因一样，它代表了从细胞启动子表达的截断的前病毒。

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.