SELECTIVE FORCES OPERATIVE IN FELV INFECTION

选择性力量在FELV感染中发挥作用

• 批准号: 6702206
• 负责人: Laura S Levy
• 金额: $ 23.13万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-28 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6702206
• 关键词: binding sites; cats; chemical structure function; feline leukemia /sarcoma virus; gene induction /repression; laboratory mouse; lymphoma; natural selections; nucleic acid repetitive sequence; protooncogene; transcription factor; transposon /insertion element; virus genetics; virus related neoplasm /cancer; virus replication

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.

逆转录病毒与其他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，病毒种群不断受到选择力的影响。 微小的基因组变异可以显著改变病毒表型，从而提供选择压力作用的底物。我们对自然逆转录病毒感染中驱动选择的病毒表型方面的理解是有限的。 猫白血病病毒（FeLV）是一个很好的模型，探索选择压力操作自然逆转录病毒感染，因为FeLV是一种自然发生的逆转录病毒地方病的远系繁殖的哺乳动物物种，家猫。FeLV是一个基因复杂的病毒家族，感染与临床变量的结果。 在这些方面，FeLV感染模拟了人类的病毒感染。 在先前的研究中，在多中心型非胸腺淋巴瘤中鉴定出一种独特的FeLV分离株，称为FeLV-945。 FeLV-945含有独特的序列元件，这些元件在地理聚类中的独立分离株中精确保守。 根据初步研究的结果，假设了可能解释FeLV-945的精确保守性和表型优势的特定机制。 具体而言，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/或感染细胞的存活优势。 为了检测这种可能性，将在感染期间纵向定量感染组织中的病毒复制，并鉴定淋巴瘤中FeLV-945激活的原癌基因。 进一步假设，需要特异性蛋白结合FeLV-945 LTR的独特序列元件可促进其精确保守。 这种可能性将通过对独特序列元件中的蛋白质结合位点进行结构和功能分析来测试。 最后，假设FeLV-945 SU的独特序列元件在改变受体相互作用和/或生长动力学方面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。 将在自然多中心淋巴瘤中FeLV变异范围的背景下考虑结果。