Selective Forces Operative in FeLV Infection

描述（由申请方提供）：γ逆转录病毒代表一组哺乳动物致癌逆转录病毒，通常与天然宿主中白血病和淋巴瘤的长潜伏期诱导相关。猫白血病病毒（FeLV）是一种天然存在的γ逆转录病毒，在自然界中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家族密切相关的病毒。这种变异的结果是遗传多样性的病毒群体，其在体内被选择压力不断塑造，并且变体作为优势种出现。我们先前描述了一种FeLV分离株，称为FeLV-945，是自然感染动物地理群中非T细胞疾病的主要种属。先前的研究证明了FeLV-945特有的LTR和SU基因的独特生物学特性。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，并作为一种新的疾病谱的决定因素。在三个特定目标中提出了研究，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拟确定FeLV-945独特的LTR和SU基因在天然宿主中的疾病决定作用。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-945 SU的受体结合特性如何影响疾病进展。目的2：探讨造血祖细胞凋亡危机的发生机制及随后存活细胞群的形成。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设。目的3：探讨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淋巴细胞分化的机制。 项目与公共卫生的相关性：拟定的FeLV介导的疾病诱导分析为研究远交哺乳动物宿主在感染天然病原体期间的发病机制提供了难得的机会。此外，所提出的工作是重要的了解早期阶段的诱导恶性肿瘤的动物模型中检查的过程。

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.