HTLV INFECTION ON HEMATOPOIESIS

描述：成人T细胞白血病(ATL)的发生与 人类围产期或出生后HTLV-1感染与 胸腺可能是建立和维持的关键靶器官 感染的可能性。HTLV可高效感染人造血祖细胞 (CD34+)细胞和这些干细胞在植入后传播病毒感染 植入SCID-HU小鼠体内的人胸腺。这项提案的目标是 是描述胸腺和胸腺感染HTLV的事件的特征 建立病毒性白血病的体内致病模型。此外， HTLV Tax1或Tax2癌基因将被转导入造血干细胞 细胞，使用逆转录病毒表达载体，以评估税收的影响 造血干细胞在体外和体内的分化。它是 假设持续的HTLV-1或-2感染的建立 和/或在CD34+细胞和前胸腺细胞中的Tax基因表达导致 淋巴生成的紊乱，这是一种诱因 白血病的发生。这项建议的具体目标是：1.建立 HTLV-1和HTLV-2在人CD34+细胞中的感染 描述其对造血的影响。HTLV感染CD34+细胞的实验研究 将被分析以量化对干细胞分化的影响 并确定病毒基因在体外是否保持表达 分化的子代细胞。2.研究HTLV感染对机体的影响 T淋巴细胞在体内的生成。感染CD34+的SCID-Hu小鼠的重建 细胞将确定高水平HTLV的建立是否会扰乱 胸腺中T细胞的发育以及这些小鼠是否发育 白血病。3.确定税收表达在分化中的作用 造血祖细胞的体外培养及对人的转化作用 体内的胸腺细胞。高效地将税收基因转化为 CD34+细胞将通过逆转录病毒的伪分型表达来完成 VSV-G包膜载体及选择转导干细胞进行检测 Tax是否可以在体内改变人类胸腺细胞。

DESCRIPTION: The development of adult T cell leukemia (ATL) correlates with HTLV-1 infection at the perinatal or postnatal stage in humans and the thymus may be a critical target organ in the establishment and maintenance of infection. HTLV can productively infect human hematopoietic progenitor (CD34+) cells and these stem cells transmit viral infection when implanted into the human thymus engrafted in SCID-hu mice. The goal of this proposal is to characterize the events involved in HTLV infection in the thymus and to establish an in vivo model of viral leukemogenesis. Additionally, the HTLV tax1 or tax2 oncogenes will be transduced into hematopoietic stem cells, using retroviral expression vectors, to evaluate the effect of Tax on the differentiation of hematopoietic stem cells in vitro and in vivo. It is hypothesized that the establishment of persistent HTLV-1 or -2 infection and/or tax gene expression in CD34+ cells and prothymocytes results in the perturbation of lymphopoiesis and that this is a predisposing factor for leukemogenesis. The Specific Aims of this proposal are: 1. Establish HTLV-1 and -2 infection in human hematopoietic progenitor (CD34+) cells and characterize the effects on hematopoiesis. HTLV infection of CD34+ cells will be analyzed to quantify the effect on the differentiation of stem cells in vitro and to determine if viral gene expression is maintained in differentiated progeny cells. 2. Study the effect of HTLV infection on T-Iymphopoiesis in vivo. Reconstitution of SCID-hu mice with infected CD34+ cells will determine if establishment of high levels of HTLV can perturb the development of T cells in the thymus and whether these mice develop leukemia. 3. Determine the role of tax expression on the differentiation of hematopoietic progenitor cells in vitro and on transformation of human thymocytes in vivo. High-efficiency transduction of the tax genes into CD34+ cells will be accomplished by pseudotyping retroviral expression vectors with VSV-G envelope and selecting transduced stem cells to test whether Tax can transform human thymocytes in vivo.