EFFECT OF HEMATOPOIETIC CYTOKINES ON RHESUS MONKEY MODEL OF AIDS

SPID编号：16 贫血、粒细胞减少和血小板减少在HIV中很常见 感染，但其发病机制还不清楚。 骨髓 低增殖（无效造血）可能是主要的 导致这些血液学畸变的病因，并且可能是 由于干细胞感染或基质细胞感染， 良好的微环境，以支持骨髓生长。 这种增长 是一个复杂的过程，需要初级和次级集落刺激 因子、营养素和细胞接触。 此外，有毒， 如果最佳，则不得存在抑制和免疫因子 造血是可以预期的。在SIV感染恒河猴的研究中， 我们已经描述了外周血细胞减少，阶段相关的CFU-GM和 BFU-E低增殖，CD 34+祖细胞中不存在感染， 用高剂量的IL-3和GM-CSF部分恢复CFU生长，和 HIV分泌的恒河猴骨髓抑制剂的存在 感染的H9细胞。 这些数据表明SIV感染的相似性 猴子对艾滋病毒感染的人类，表明无效的造血， 与细胞动力学和可能的抑制异常，是一个因素， 支持使用该模型研究细胞因子的作用 局在此，我们提出了一个全面的研究， 外源性细胞因子对血液学和病毒学影响 在实验感染SIV的恒河猴中施用。 这 模型是有利的，因为它1）允许测试动物（没有 伴随抗病毒治疗），2）使研究者能够了解 感染，3）具有明确的疾病进展，4） 初步数据表明，血液学 SIV感染的后果与HIV感染的后果非常相似。 具体地说，我们将研究外源性施用 细胞因子对造血区室扩增的影响，细胞因子对造血区室扩增的影响， 感染、病毒复制和细胞因子后负荷 局 我们将利用隔室特异性细胞因子，测试 在感染淋巴细胞或单核细胞的猴子中，SIV占优势 株 预计通过这些目标， SIV感染的猕猴中的细胞因子的水平可以证明，任何不利的 可以阐明细胞因子对病毒复制的影响，并且可以建立一个模型， 可以表征未来的细胞因子、骨髓转运， 基因治疗实验

SPID#: 16 Anemia, granulocytopenia, and thrombocytopenia are common in HIV infection though their pathogenesis is not well understood. Bone marrow hypoproliferation (ineffective hematopoiesis) is likely to be a main contributor to the etiology of these hematologic aberrations, and may be due to stem cell infection, or stromal cell infection with loss of a satisfactory microenvironment to support bone marrow growth. This growth is a complex process requiring primary and secondary colony stimulating factors, nutrients, and cellcell contact. In addition, toxic, inhibitory, and immune factors must not be present if optimal hematopoiesis is expected. In studies of SIV infected rhesus macaques, we have described peripheral blood cytopenias, stage-related CFU-GM and BFU-E hypoproliferation, absence of infection in CD34+ progenitors, partial restoration of CFU growth with high doses of IL-3 and GM-CSF, and the presence of an inhibitor of rhesus bone marrow secreted by HIV infected H9 cells. These data show the similarity of SIV infected monkeys to HIV infected humans, suggest that ineffective hematopoiesis, with cytokinetic and possibly inhibitory abnormalities, is a factor and support the use of this model for studying the effects of cytokine administration. Herein, we propose a comprehensive study of the hematologic and virologic consequences of exogenous cytokine administration in rhesus macaques experimentally infected with SIV. This model is advantageous as it 1) allows testing of animals (without concomitant antiviral therapy), 2) allows investigators to know the time of infection, 3) has a well-defined disease progression and 4) is supported by preliminary data which suggest that the hematologic consequences of SIV infection are very similar to those of HIV. Specifically, we will study the effects of exogenously administered cytokines on hematopoietic compartment expansion, sites of cellular infection, and viral replication and burden following cytokine administration. We will utilize compartment specific cytokines, tested in monkeys infected with a lymphocyte or a monocyte predominate SIV strain. It is expected that, through these aims, the positive effects of cytokines in SIV infected macaques can be demonstrated, any untoward effects of cytokines on viral replication can be elucidated, and a model can be characterized for future cytokine, bone marrow transportation, and gene therapy experiments.