HUMAN IMMUNODEFICIENCY VIRUS AND HEMATOPOIESIS

目前尚不确定是否造血功能缺陷的特点， 人类免疫缺陷病毒（HIV）感染是由于受损 造血集落刺激因子（CSF）的产生。 造血祖细胞感染，HIV诱导的抑制 抗体或其它蛋白质，或这些损伤的组合。我们 广泛的目标是确定这些发病机制中的哪一种 是最重要的人类免疫缺陷病毒嗜CD 4 阳性辅助/诱导T淋巴细胞和单核细胞。枯竭和 CD 4阳性T细胞的功能损害是免疫缺陷的标志。 疾病，同时也描述了单核细胞的功能缺陷。 T细胞可能是多细胞生成素白细胞介素3的唯一来源 （IL-3），一种对肿瘤细胞的存活和增殖具有深远影响的CSF， 造血祖细胞：与单核细胞和骨髓一起 基质细胞，T细胞也产生第二种多细胞生成素，粒细胞- 巨噬细胞集落刺激因子（GM-CSF）。除了几个CSF，单核细胞产生 几种单核因子如白细胞介素1（IL-1）和肿瘤坏死因子 (TNF)，CSF表达的重要诱导剂。具体而言，我们希望 测定10例HIV感染者IL-3和GM-CSF的合成能力 患者T细胞和用以下物质诱导后建立的T细胞系 凝集素、佛波醇酯或IL-1和T细胞受体交联，和2） 患者单核细胞的单核因子和CSF合成能力，以及CSF 患者基质细胞对这些单核因子的反应性。为这些 研究中，我们将通过生物测定分析CSF蛋白表达， 免疫测定和通过北方技术的RNA表达，RNA酶 保护分析和/或原位杂交。如果IL-3或GM受损， CSF的合成，我们计划研究基因的机制， HIV感染的T细胞系中的失调， 结合IL-3和GM-CSF基因组克隆的确定的调节区域。我们 还计划使用高度富集的正常和患者祖细胞， 3)评估推定抑制分子的作用机制，以及 4)比较它们对纯化的重组CSF的反应性， 单独和组合：这些试验将在 存在或不存在抗病毒剂。我们的长期目标是 HIV感染者造血功能缺陷的发病机制 患者，将导致改善管理，包括适当的 GSF的选择，可用于治疗这些中观察到的血细胞减少症， 患者

It is uncertain whether the hematopoietic deficiency that characterizes human immunodeficiency virus (HIV) infection is due to impaired production of the hematopoietic colony stimulating factors (CSFs). Infection of hematopoietic progenitor cells, suppression induced by HIV antibodies or other proteins, or a combination of these insults. Our broad objectives are to establish which of these pathogenetic mechanisms are most important. The human immunodeficiency virus is tropic for CD4 positive helper/inducer T lymphocytes and monocytes. Depletion and functional impairment of CD4 positive T cells is a hallmark of the disease, while functional defects of monocytes have also been described. T cells are probably the only source of the multi-poietin interleukin 3 (IL-3), a CSF with profound effects on the survival and proliferation of hematopoietic progenitor cells: together with monocytes and bone marrow stromal cells, T cells also produce a second multipoietin, granulocyte- macrophage CSF (GM-CSF). In addition to several CSFs, monocytes produce several monokines such as interleukin 1 (IL-1) and tumor necrosis factor (TNF), important inducers of CSF expression. Specifically, we wish to determine 10 the IL-3 and GM-CSF synthetic capacity of HIV infected patient T cells and established T cell lines after induction with lectins, phorbol esters or IL-1 and T cell receptor crosslinking, and 2) the monokine and CSF synthetic capacity of patient monocytes, and the CSF responsiveness of patient stromal cells to these monokines. for these studies, we will analyze CSF protein expression by bioassay and immunoassay and RNA expression by the Northern technique, RNAse protection analysis and/or in situ hybridization. If impaired IL-3 or GM- CSF synthesis is found, we plan to investigate the mechanism of gene dysregulation in HIV infected T cell lines by analyzing the proteins that bind to defined regulatory regions of IL-3 and GM-CSF genomic clones. We also plan to use highly enriched normal and patient progenitor cells to 3) evaluate the mechanism of action of putative suppressor molecules, and 4) compare their responsiveness to purified recombinant CSFs tested both singly and in combination: these assays will be carried out in the presence or absence of antiviral agents. Our long term aim is to obtain insight into the pathogenesis of the hematopoietic defect in HIV infected patients that will lead to improved management, including an appropriate choice of GSFs that can be used to treat the cytopenias observed in these patients.