HIV AND HEMOPOIETIC MICROENVIRONMENT

HIV与造血微环境

• 批准号: 3242921
• 负责人: Kenneth S. Zuckerman
• 金额: $ 16.6万
• 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/3242921
• 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.

造血缺陷是一个主要部分的临床图片， 患者感染艾滋病病毒，艾滋病病毒，显然独立 潜在的继发感染或化疗。 中 可能导致这些结果的机制是：（1） 造血祖细胞感染和直接损伤;以及 (2)副细胞的感染和损伤， 多种造血生长因子（HGF）和细胞外 基质（ECM）大分子，这是必要的支持和 促进造血干细胞存活、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 由于艾滋病毒可以感染 单核细胞/巨噬细胞在体内和体外，可能可以感染 内皮细胞，并且至少可以在转染的 成纤维细胞，这些逆转录病毒可能能够引起 严重破坏这些基质细胞的正常功能， 从而导致正常造血功能受损。 我们将 研究HIV感染患者的基质细胞， 体外感染正常和活化的 单核细胞/巨噬细胞、内皮细胞和骨髓成纤维细胞 用活的HIV和分离株的重组实验室构建物 艾滋病毒感染者的造血支持 功能协调发展的 最后，我们将使用特异性抗体 抗HIV包膜糖蛋白或CD 4，和定点穆塔- HIV包膜的起源和反式作用基因改变了 艾滋病毒感染、复制并导致功能障碍 造血基质细胞和辅助细胞。