MECHANISM OF HEMATPOIETIC SUPPRESSION IN HIV-1 INFECTION

HIV-1感染的造血抑制机制

• 批准号: 3361015
• 负责人: Ronald Hoffman
• 金额: $ 20.3万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-12-01 至 1993-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3361015
• 关键词: AIDS; Betaherpesvirinae; HIV infections; Parvoviridae; bone marrow; cell mediated cytotoxicity; cell population study; flow cytometry; growth factor; hematopoiesis; hematopoietic stem cells; hematopoietic tissue; human immunodeficiency virus 1; human subject; human tissue; immunofluorescence technique; natural gene amplification; nucleic acid hybridization; virus envelope; virus infection mechanism; virus protein

Infection with human immunodeficiency virus type-I (HIV-1) is complicated by a variety of hematological abnormalities including leukopenia, anemia and thrombocytopenia. Many factors in AIDS patients including active infections, secondary neoplasms, or simultaneous administration of antibiotics and/or cytotoxic drugs can contribute to the severity of this hematopoietic cellular failure. In this application we will attempt to determine, in part, the pathogenesis of the hematopoietic cellular failure in AIDS patients by determining the consequences of HIV-1 infection on both human hematopoietic progenitor cells and stem cells. In addition, the effect of two other viral pathogens, cytomegalovirus (CMV) and the human parvovirus B19 (HPV-B19) on hematopoiesis in AIDS patients will also be examined. As a consequence of the severe immunodeficiency that occurs in AIDS, latent infections with CMV might be reactivated and/or normal host responses to HPV-B19 blunted. Viremia with either of these agents might thus be implicated as contributory factors to hematopoietic suppression in this patient population. To accomplish these goals, we propose to pursue the following specific aims: 1. Determine whether HIV-1 can directly infect human hematopoietic progenitors cells and/or stem cells in vitro. Detect the presence of HIV-1 in marrow elements from AIDS patients. 2. Determine whether autoimmune phenomena in AIDS patients lead to destruction of hematopoietic progenitor cells or stem cells. These autoimmune phenomena might be directed against antigens that are a direct consequence of HIV-1 infection or be due to adsorption of HIV-1 envelope proteins on cell surfaces of progenitor cells. Both of these mechanisms might result in immune clearance or elimination of hematopoietic cells by means of antibody-dependent cytotoxicity. 3. Determine the effect of HPV-B19 and CMV on normal human hematopoietic progenitor cells and stem cells and compare that with the effect of these viruses on similar cell populations obtained from HIV-1 infected patients. Determine whether progenitor cells from AIDS patients are infected with either of these two viruses. The accomplishment of these goals will allow us to further define important components of the multifactorial origin of hematopoietic suppression in AIDS.

人类免疫缺陷病毒I型（HIV-1）的感染很复杂 通过各种血液学异常，包括白细胞减少，贫血 和血小板减少症。 艾滋病患者的许多因素包括活跃 感染，继发性肿瘤或同时给药 抗生素和/或细胞毒性药物可能会导致这种严重性 造血细胞衰竭。 在此应用程序中，我们将尝试 部分确定造血细胞的发病机理 通过确定HIV-1的后果，艾滋病患者失败 人类造血祖细胞和干细胞上的感染。 另外，另外两种病毒病原体的影响，巨细胞病毒 （CMV）和艾滋病中造血的人类细小性病毒B19（HPV-B19） 还将检查患者。 由于严重 艾滋病中发生的免疫缺陷，CMV的潜在感染可能是 重新激活和/或正常宿主对HPV-B19的反应钝。 病毒血症 因此，与这两种代理有关 该患者人群中造血抑制的因素。 到 实现这些目标，我们建议追求以下特定目标： 1。确定HIV-1是否可以直接感染人类造血 祖细胞和/或干细胞体外。 检测 艾滋病患者的骨髓元素中的HIV-1。 2。确定是否 艾滋病患者的自身免疫现象导致 造血祖细胞或干细胞。 这些自身免疫现象 可能针对HIV-1直接结果的抗原 感染或由于HIV-1包膜蛋白在细胞上的吸附 祖细胞的表面。 这两种机制都可能导致 免疫清除率或消除造血细胞 抗体依赖性细胞毒性。 3。确定HPV-B19和 在正常人造血祖细胞和干细胞上的CMV以及 将这些病毒对相似细胞群的影响进行比较 从HIV-1感染的患者获得。 确定祖先是否 来自艾滋病患者的细胞被这两种病毒中的任何一种感染。 这些目标的实现将使我们能够进一步定义 造血的多因素起源的重要组成部分 在艾滋病中抑制。