HTLV INFECTION ON HEMATOPOIESIS

HTLV 感染对造血功能的影响

• 批准号: 2896444
• 负责人: GEROLD FEUER
• 金额: $ 10.04万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-16 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2896444
• 关键词: SCID mouse; T lymphocyte; cell differentiation; flow cytometry; gene expression; genetic transduction; hematopoiesis; hematopoietic stem cells; human T cell lymphotropic virus type 1; human T cell lymphotropic virus type 2; human fetus tissue; neoplastic transformation; oncogenes; polymerase chain reaction; thymus; tissue /cell culture; viral leukemogenesis

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.

描述：成人T细胞白血病（ATL）的发展与 人类围产期或产后阶段的HTLV-1感染和 胸腺可能是建立和维护的关键目标器官 感染。 HTLV可以有效地感染人类造血祖细胞 （CD34+）细胞和这些干细胞植入时会传播病毒感染 进入SCID-HU小鼠中的人胸腺。 该提议的目标 是为了表征胸腺中HTLV感染涉及的事件， 建立病毒性白血病的体内模型。 另外， HTLV税务1或税收2癌基因将被转导为造血茎 使用逆转录病毒表达向量的细胞评估税收对 体外和体内造血干细胞的分化。 这是 假设建立持续的HTLV -1或-2感染 和/或税收基因表达在CD34+细胞和泼妇细胞中导致 淋巴管的扰动，这是一个诱发因素 白血病。 该提案的具体目的是：1。 人造血祖细胞（CD34+）细胞中的HTLV -1和-2感染 表征对造血的影响。 CD34+细胞的HTLV感染 将分析以量化对干细胞分化的影响 体外，确定病毒基因表达是否保持在 分化的后代细胞。 2。研究HTLV感染对 体内的T-二孢子。 用感染的CD34+重建SCID-HU小鼠 细胞将确定建立高水平的HTLV是否会扰动 胸腺中T细胞的发展以及这些小鼠是否发展 白血病。 3。确定税收表达对分化的作用 体外造血祖细胞的体外和人类转化 体内胸腺细胞。 税收基因的高效转导 CD34+细胞将通过假病毒表达来实现 具有VSV-G Invelope并选择转导的干细胞进行测试的向量 税收是否可以在体内转化人类胸腺细胞。