Selective Forces Operative in FeLV Infection

描述(申请人提供)：伽玛逆转录病毒代表一组哺乳动物致癌逆转录病毒，通常与在自然宿主中诱导白血病和淋巴瘤的长潜伏期有关。猫白血病病毒(FeLV)是一种自然产生的伽马逆转录病毒，在自然界中发现不是作为一个单一的基因组物种，而是作为一个基因复杂的密切相关的病毒家族。这种变异的结果是一个遗传多样性的病毒种群，它不断地受到体内选择压力的塑造，并由此产生变异，成为优势物种。我们之前描述了一种FeLV分离株，命名为FeLV-945，在自然感染动物的地理集群中，作为非T细胞疾病的优势物种。以往的研究表明，FeLV-945独特的LTR和SU基因特征具有独特的生物学特性。这些序列元件被证明赋予病毒复制优势，改变与宿主细胞受体的相互作用，并作为新的疾病谱的决定因素。研究提出了三个特定的目标，以确定它们在感染和发病机制中的作用和作用机制。目的1确定FeLV-945独特的LTR和SU基因在自然宿主疾病决定中的作用。将进行实验，以确定FeLV-945 LTR是否在体内具有复制优势，以及FeLV-945Su的受体结合特性如何影响疾病进展。目的2探讨造血祖细胞最初的凋亡危机和随后存活群体的出现的机制。这些研究将利用早期造血祖细胞分化的组织培养模型来测试关于P53的作用及其在疾病过程早期的抑制的新假说。目的3研究感染改变疾病早期造血祖细胞分化的机制。特别是，实验将集中在感染改变B淋巴样细胞分化的机制上。 该项目与公共卫生的相关性：拟议的FeLV介导的疾病诱导分析提供了一个难得的机会来研究在自然病原体感染期间繁殖的哺乳动物宿主的致病机制。此外，这项拟议的工作对于通过检查动物模型中的过程来理解恶性诱导的早期阶段是重要的。

DESCRIPTION (provided by applicant): The gammaretroviruses represent a group of mammalian oncogenic retroviruses typically associated with the long-latency induction of leukemia and lymphoma in the natural host. Feline leukemia virus (FeLV), a naturally occurring gammaretrovirus, is found in nature not as a single genomic species but as a genetically complex family of closely related viruses. The consequence of this variation is a genetically diverse virus population that is continuously shaped by selective pressures in vivo and from which variants arise as predominant species. We previously described an isolate of FeLV, termed FeLV-945, as the predominant species in non-T-cell diseases in a geographic cluster of naturally infected animals. Previous studies demonstrated distinctive biological properties of the unique LTR and SU gene characteristic of FeLV-945. These sequence elements were shown to confer a replicative advantage to the virus, to alter interactions with the host cell receptor, and to act as determinants of a novel disease spectrum. Studies are proposed in three Specific Aims to determine their role and mechanisms of action in infection and pathogenesis. Aim 1 proposes to determine the roles of the unique LTR and SU gene of FeLV-945 in disease determination in the natural host. Experiments will be performed to determine whether the FeLV-945 LTR confers a replicative advantage in vivo, and how the receptor-binding properties of FeLV-945 SU influence disease progression. Aim 2 proposes to explore the mechanism of initial apoptotic crisis in hematopoietic progenitors and the subsequent emergence of a surviving population. These studies will utilize a tissue culture model of early hematopoietic progenitor cell differentiation to test a novel hypothesis about the role of p53 and its suppression early in the disease process. Aim 3 proposes to investigate the mechanisms by which infection alters the differentiation of hematopoietic progenitors early in the disease process. In particular, experiments will focus on the mechanism by which infection alters B-lymphoid cell differentiation. Relevance of the Project to Public Health: The proposed analysis of FeLV-mediated disease induction offers a rare opportunity to study mechanisms of pathogenesis in an outbred mammalian host during infection with a natural pathogen. Further, the proposed work is important for understanding the early stages of the induction of malignancy by examining the process in an animal model.