SELECTIVE FORCES OPERATIVE IN FELV INFECTION

逆转录病毒和其他RNA病毒一样，在自然界中不是作为单一的基因组物种存在，而是作为密切相关的基因组的复杂混合物存在。在自然宿主感染期间，病毒种群不断地受到选择性力量的影响。微小的基因组变异可能会显著改变病毒的表型，从而提供选择性压力作用的底物。我们对在自然逆转录病毒感染中驱动选择的病毒表型方面的了解是有限的。猫白血病病毒(FeLV)是一种自然产生的逆转录病毒，在近亲繁殖的哺乳类动物家猫中流行，因此是探索自然逆转录病毒感染中选择性压力的极佳模型。FeLV是一个基因复杂的病毒家族，其感染与临床预后相关。在这些方面，FeLV感染与人类的病毒感染相似。在以前的研究中，在多中心型的非胸腺淋巴瘤中发现了一种独特的FeLV分离株，称为FeLV-945。FeLV-945包含独特的序列元件，这些元件在地理簇中的独立分离物中精确保守。根据初步研究的结果，提出了可能解释FeLV-945的精确保守性和明显的表型优势的具体机制。具体地说，假设FeLV-945的独特结构特征赋予病毒在体内的选择性生长优势，和/或感染细胞的生存优势。为了测试这种可能性，将在感染期间对感染组织中的病毒复制进行纵向量化，并将确定淋巴瘤中由FeLV-945激活的原癌基因。进一步的假设是，特定的蛋白质与FeLV-945 LTR的独特序列元件结合的要求促进了其精确保守。这种可能性将通过对独特序列元件中蛋白质结合位点的结构和功能分析来测试。最后，假设FeLV-945SU的独特序列元件在改变的受体相互作用和/或生长动力学中具有选择性表型优势。这种可能性将使用一种新的单周期感染试验进行测试。这一结果将结合自然多中心淋巴瘤的FeLV变异范围来考虑。

Retroviruses, like other RNA viruses, exist in nature not as a single genomic species, but as a complex mixture of closely related genomes. During infection in the natural host, the virus population is continually shaped by selective forces. Minor genomic variations may significantly alter the virus phenotype, and thus provide the substrate on which selective pressures act. Our understanding of the aspects of virus phenotype that drive selection in natural retroviral infection is limited. Feline leukemia virus (FeLV) is an excellent model with which to explore the selective pressures operative in natural retroviral infection because FeLV is a naturally occurring retrovirus endemic in an outbreeding mammalian species, the domestic cat. FeLV is a genetically complex family of viruses, infection with which is associated with clinically variable outcome. In these respects, FeLV infection emulates viral infection in humans. In previous studies, a unique FeLV isolate, termed FeLV-945, was identified in non-thymic lymphomas of the multicentric type. FeLV-945 contains unique sequence elements that are precisely conserved among independent isolates in a geographic cluster. Based on the results of preliminary studies, specific mechanisms are hypothesized that may account for the precise conservation and apparent phenotypic advantage of FeLV-945. Specifically, it is hypothesized that the distinctive structural features of FeLV-945 confer a selective growth advantage to the virus in vivo, and/or a survival advantage to the infected cell. To test this possibility, virus replication will be quantified in infected tissues longitudinally during infection, and proto-oncogenes activated by FeLV-945 in lymphomas will be identified. It is further hypothesized that a requirement for specific protein binding to the unique sequence elements of the FeLV-945 LTR promotes its precise conservation. This possibility will be tested through a structural and functional analysis of protein binding sites in the unique sequence elements. Finally, it is hypothesized that the unique sequence elements of FeLV-945 SU confer a selective phenotypic advantage in altered receptor interactions and/or growth kinetics. This possibility will be tested using a novel single-cycle infection assay. The results will be considered in the context of the range of FeLV variation in natural multicentric lymphomas.