HTLV INFECTION ON HEMATOPOIESIS

描述：成人T细胞白血病（ATL）的发展与以下因素相关： 人类围产期或出生后阶段的HTLV-1感染以及 胸腺可能是一个关键的靶器官，在建立和维持 感染 HTLV能高效感染人造血祖细胞 (CD34+）细胞，这些干细胞在植入时会传播病毒感染 移植到SCID-hu小鼠的人胸腺中。 这项提案的目的是 是描述胸腺中HTLV感染所涉及的事件， 以建立病毒性白血病发生的体内模型。 另夕h HTLV tax 1或tax 2癌基因将被转导到造血干细胞中 细胞，使用逆转录病毒表达载体，以评估Tax对 造血干细胞的体外和体内分化。 是 假设持续性HTLV-1或-2感染的建立 和/或tax基因在CD 34+细胞和前胸腺细胞中的表达导致 干扰淋巴细胞生成，这是一个诱发因素， 白血病发生 该提案的具体目标是：1。 建立 人造血祖细胞（CD 34+）中的HTLV-1和HTLV-2感染以及 描述对造血的影响。 CD 34+细胞的HTLV感染 将进行分析，以量化对干细胞分化的影响 并确定是否在体外维持病毒基因表达， 分化的后代细胞。 2. 研究HTLV感染对 体内T淋巴细胞生成。 用感染的CD 34+重建SCID-hu小鼠 细胞将决定是否建立高水平的HTLV可以扰乱 胸腺中T细胞的发育以及这些小鼠是否发育 白血病 3. 确定税收表达对差异化的作用 造血祖细胞的体外培养和人 体内胸腺细胞。 将tax基因高效转导入 将通过假型化逆转录病毒表达完成CD 34+细胞 具有VSV-G包膜的载体，并选择转导的干细胞进行测试 Tax能否在体内转化人胸腺细胞。

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.