HIV AND HEMOPOIETIC MICROENVIRONMENT

HIV与造血微环境

• 批准号: 3242922
• 负责人: Kenneth S. Zuckerman
• 金额: $ 17.41万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-12-20 至 1993-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3242922
• 关键词: AIDS; CD4 molecule; HIV infections; antiviral antibody; bone marrow; cellular pathology; fibroblasts; glycoproteins; hematopoiesis; hematopoietic growth factor; hematopoietic stem cells; hematopoietic tissue; human immunodeficiency virus; human subject; macrophage; monocyte; provirus; site directed mutagenesis; transcription factor; transfection; vascular endothelium; virus cytopathogenic effect; virus envelope; virus genetics; virus infection mechanism; virus protein; virus replication

Defective hematopoiesis is a major part of the clinical picture in patients infected with the AIDS virus, HIV, apparently independent of underlying secondary infections or chemotherapy. Among the mechanisms that could be responsible for these findings are: (1) infection of and direct damage to hemopoietic progenitor cells; and (2) infection of and damage to accessory cells, which produce a variety of hemopoietic growth factors (HGF) and extracellular matrix (ECM) macromolecules, which are necessary for supporting and promoting hemopoietic stem cell survival, proliferation, and differentiation within the bone marrow. The overall purpose of this proposal is to determine the effects of HIV infection on hemopoietic stromal cells. Since HIV can infect monocytes/macrophages in vivo and in vitro, probably can infect endothelial cells, and at least can replicate in transfected fibroblastic cells, these retroviruses may be capable of causing serious disruption of normal functions of these stromal cells and, hence, resulting in impairment of normal hemopoiesis. We will study stromal cells from HIV infected patients and will determine the effects of in vitro infection of normal and activated monocytes/macrophages, endothelial cells and marrow fibroblasts with recombinant laboratory constructs of viable HIV and isolates of HIV from infected patients on their hemopoietic supportive functions. Finally, we will use specific antibodies directed against HIV envelope glycoprotein or CD4, and site-directed muta- genesis of HIV envelope and trans-acting genes to alter the ability of HIV to infect, replicate in, and cause dysfunction of hemopoietic stromal and accessory cells in vitro.

造血功能障碍是本病临床表现的主要部分。 感染艾滋病病毒的患者，HIV，显然是独立的 潜在的继发性感染或化疗。在这些人中 可能导致这些发现的机制是：(1) 造血祖细胞的感染和直接损伤；以及 (2)附属细胞的感染和损伤，从而产生 造血生长因子(HGF)的多样性与细胞外 基质(ECM)大分子，这是支持和 促进造血干细胞的存活、增殖和 骨髓内的分化。的总体目的 这项建议是为了确定艾滋病毒感染对 造血基质细胞。因为艾滋病毒可以感染 在体内和体外，单核/巨噬细胞可能会感染 内皮细胞，至少可以在转染体中复制 成纤维细胞，这些逆转录病毒可能会引起 这些间质细胞的正常功能严重中断， 因此，导致正常的造血功能受损。我们会 研究艾滋病毒感染者的基质细胞，并将确定 正常和活化细胞体外感染效应的研究 单核/巨噬细胞、内皮细胞和骨髓成纤维细胞 用重组的活体艾滋病毒和分离株的实验室构建 来自感染患者的HIV对他们的造血支持 功能。最后，我们将使用定向的特定抗体 抗HIV包膜糖蛋白或CD4，以及定点突变- HIV包膜和反式作用基因改变能力的起源 感染艾滋病毒，在体内复制，并导致功能障碍 体外培养的造血基质细胞和辅助细胞。