HEMATOPOIETIC SUPPRESSION IN HIV INFECTION

HIV 感染中的造血抑制

• 批准号: 2231771
• 负责人: ROBERT T MEANS
• 金额: $ 13.63万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2231771
• 关键词: 2'3' dideoxyinosine; AIDS therapy; HIV infections; anemia; antiAIDS agent; antiviral agents; autocrine; bone marrow exam; colony stimulating factor; cytokine; cytokine receptors; disease /disorder model; dosage; drug adverse effect; erythropoiesis; growth factor; hematopoietic growth factor; human subject; human therapy evaluation; immunosuppression; messenger RNA; receptor expression; zidovudine

Peripheral blood cytopenias are commonly found in infection with the human immunodeficiency virus (HIV). The cytopenias associated with HIV infection may affect the health of patients by increasing exposure to transfusions, by predisposing to bacterial infection or bleeding, or by limiting therapeutic options such as antiretroviral therapy. Suppression of hematopoiesis in HIV infection may result from infection of marrow accessory cells which support and regulate hematopoiesis, infection of hematopoietic progenitors themselves, or both. Antiretroviral therapy may exacerbate these effects. Extensive investigation has indicated that the cytokines mediating the immune response, such as interleukin-1, tumor necrosis factor, and the interferons, produce the anemia associated with chronic inflammatory disorders. These cytokine effects occur at several levels, including hematopoietic progenitor suppression and inhibition of appropriate growth factor production. The hypothesis to be tested in this proposal is that suppression of erythropoiesis in HIV infection results from the same mechanism, and that HIV infection itself may alter the susceptibility of hematopoietic progenitors to growth factors and cytokines. The hypothesis will be tested by determination of marrow cytokine levels in HIV-infected individuals; by assessment of cytokine/ growth factor responsiveness of hematopoietic progenitors from HIV patients relative to non-HIV infected individuals, including correction of cytokine mediated inhibition of erythropoiesis by hematopoietic growth factors; by evaluating the effects of antiretroviral agents on cytokine/growth factor responsiveness of hematopoietic progenitors from HIV patients relative to non-HIV infected individuals; and by determining the effects of antiretroviral agents on erythropoietin binding to highly purified human erythroid progenitors. The approach proposed in these studies will provide new insight into the mechanisms of hematopoietic suppression in HIV infection, and potentially direct research into therapeutic modalities resulting in enhanced quality of life for these patients.

外周血细胞质症通常在人类感染中发现 免疫缺陷病毒（HIV）。与HIV感染相关的细胞质减少症 可能会通过增加输血的暴露来影响患者的健康 通过倾向于细菌感染或出血，或通过限制 治疗选择，例如抗逆转录病毒疗法。 抑制 HIV感染中的造血作用可能是由于骨髓的感染而引起的 支持和调节造血的辅助细胞，感染 造血祖细胞本身或两者兼而有之。抗逆转录病毒疗法可能 加剧这些影响。广泛的调查表明 细胞因子介导免疫反应，例如白介素-1，肿瘤 坏死因子和干扰素会产生与 慢性炎症性疾病。这些细胞因子作用发生在几个 水平，包括造血祖细胞抑制和抑制 适当的生长因子产生。在此要检验的假设 提议是抑制艾滋病毒感染结果中红细胞生成的抑制 从相同的机制中，艾滋病毒感染本身可能会改变 造血祖细胞对生长因素和 细胞因子。 该假设将通过测定骨髓来检验 艾滋病毒感染者的细胞因子水平；通过评估细胞因子/ 来自HIV患者的造血祖细胞的生长因子反应性 相对于非HIV感染的个体，包括细胞因子的校正 造血生长因子介导了促红细胞生成的抑制作用；经过 评估抗逆转录病毒对细胞因子/生长因子的影响 来自HIV患者的造血祖细胞的反应性相对于 非HIV感染的个体；并确定 红细胞生成素与高度纯化的人结合的抗逆转录病毒药物 红细胞祖细胞。这些研究中提出的方法将提供 对艾滋病毒造血抑制机制的新见解 感染，并有可能直接研究治疗方式 这些患者的生活质量提高。