GENETIC ASPECTS OF VIRAL ONCOGENESIS IN WILD MOUSE SPECIES

不同的野鼠和近交系小鼠对逆转录病毒和逆转录病毒引起的疾病的易感性各不相同。这些差异是由于特定的小鼠染色体基因的等位基因差异所致，我们一直在进行一项持续的努力，以确定和表征与这种耐药性有关的小鼠基因。今年，我们继续研究病毒抗性基因Fv1，它负责对所有嗜鼠的MLV产生部分抗性。该基因的一个等位基因nr控制着对所有B嗜性病毒和一些N嗜性病毒的抗性。我们对Fv1介导的抗性靶标AKR-L1的病毒衣壳基因进行了测序。我们鉴定了一个单一氨基酸的差异，并使用定点突变来确认这种变化与nr表型有关。这个站点不同于我们之前确定的对N嗜性和B嗜性病毒的相对抗性负责的站点。我们还鉴定了一种在大多数小鼠身上发现的能灭活白血病病毒的血清因子。我们已经证明，该因子不会灭活生态型和两性型宿主范围组的病毒，而是强烈地灭活多嗜性病毒，而不是强烈地灭活异嗜性病毒。我们已经确定该因子的存在是受单基因控制的，并使用基因组扫描来确定负责基因座的图谱位置。我们已经确定了两个映射到该区域的基因，作为血清因子的可能候选基因。在其他研究中，我们已经确定了一个新的染色体位置，在肿瘤组织中发现了整合病毒，表明存在一个与肿瘤转化有关的新基因。最后，我们还继续努力确定抗性基因Rmcf的特征，该基因负责对MLV多变型的部分抗性。我们现在已经克隆了与Rmcf相关的病毒包膜的染色体整合副本，并正在进行测序，以确定该包膜是否是完整逆转录病毒的一部分，或者是否像类似的FV-4抗性基因一样，它代表了从细胞启动子表达的截短的前病毒。

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.