HUMAN IMMUNODEFICIENCY VIRUS AND HEMATOPOIESIS

目前尚不确定的是，以造血功能不足为特征的 人类免疫缺陷病毒(HIV)感染是由于受损 产生造血祖细胞集落刺激因子(CSF)。 HIV诱导的造血祖细胞感染和抑制 抗体或其他蛋白质，或这些侮辱的组合。我们的 总体目标是确定这些致病机制中的哪一种 是最重要的。人类免疫缺陷病毒对cd4有嗜性。 阳性辅助性/诱导性T淋巴细胞和单核细胞。耗尽和 CD4+T细胞功能障碍是慢性粒细胞白血病 疾病，而单核细胞的功能缺陷也已被描述。 T细胞可能是多种促红细胞生成素白介素3的唯一来源 (IL-3)，一种对细胞存活和增殖有深远影响的脑脊液 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聚生成素，粒细胞- 巨噬细胞集落刺激因子(GM-CSF)。除了几种CSF外，单核细胞还会产生 几种单因子，如白介素1和肿瘤坏死因子 (肿瘤坏死因子)是脑脊液表达的重要诱导物。具体来说，我们希望 HIV感染者IL-3和GM-CSF合成能力的测定 患者T细胞及诱导后建立的T细胞系 凝集素、佛波酯或IL-1和T细胞受体交联物，以及2) 患者单核细胞单核细胞和脑脊液合成能力及脑脊液 患者间质细胞对这些单核细胞的反应性。对于这些 研究，我们将通过生物测定和分析脑脊液蛋白的表达 用Northern核糖核酸酶技术进行免疫分析和RNA表达 保护分析和/或原位杂交。如果IL-3或GM受损- 发现了脑脊液的合成，我们计划研究基因的作用机制 通过分析感染HIV的T细胞株中 结合IL-3和GM-CSF基因组克隆的特定调控区域。我们 还计划使用高度浓缩的正常和患者祖细胞来 3)评估可能的抑制分子的作用机制，以及 4)比较它们对纯化的重组CSF的响应性 单独和组合：这些检测将在 是否有抗病毒药物。我们的长期目标是获得 HIV感染者造血缺陷发病机制的研究进展 将导致改善管理的患者，包括适当的 可用于治疗这些患者中的细胞减少症的GSFS的选择 病人。

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.