HEMATOPOIETIC CYTOKINES EFFECT ON A MODEL OF AIDS

描述（改编自申请人摘要）贫血， 粒细胞减少症、淋巴细胞减少症和血小板减少症在HIV中是常见的。 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 生长是一个复杂的过程， 刺激因子、营养素和细胞：细胞接触。 此外，本发明还提供了一种方法， 如果最佳，则不得存在毒性、抑制性和免疫因子 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， 以及HIV分泌的抑制剂或恒河猴骨髓的存在 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，研究人员提出了一项全面的研究， 外源性细胞因子的血液学和病毒学后果 在实验感染SIV的恒河猴中施用。 该模型是有利的，因为I（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 感染时间，（3）有一个明确的疾病进展， 补助期，（4）是由初步数据支持，建议 SIV感染的血液学后果与 那些艾滋病毒。 具体来说，研究人员建议研究 外源性细胞因子对造血区室的影响 扩增、细胞感染部位以及病毒复制和负荷 细胞因子给药后。 调查人员将利用 室特异性细胞因子，在感染a 淋巴细胞或单核细胞占优势的SIV株。 预计， 通过这些目的，细胞因子在SIV感染中的积极作用， 可以证明，细胞因子对病毒的任何不利影响， 复制可以被阐明，模型可以被表征为 未来的细胞因子、骨髓转运和基因治疗 实验 本报告建议的研究将需要以下方面的努力： 一组有着广泛合作经验的调查员， 在造血、免疫和 SIV感染的病毒学方面，以及动物模型中细胞因子的使用。

DESCRIPTION (Adapted from the applicant's abstract) Anemia, granulocytopenia, lymphopenia, 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 cell:cell 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 or 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, the investigators propose a comprehensive study of the hematologic an virologic consequences of exogenous cytokine administration in rhesus macaques experimentally infected with SIV. this model is advantageous as i (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 in the grant period, and (4) is supported by preliminary data which suggest that the hematologic consequences of SIV infection are very similar to those of HIV. Specifically, the investigators propose to study effects of exogenously administered cytokines on hematopoietic compartment expansion, sites of cellular infection, and viral replication and burden following cytokine administration. The investigators 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. The studies proposed herein will require the efforts of a team of investigators with extensive previous collaborations, experience, and expertise in the areas of hematopoietic, immunologic, and virologic aspects of SIV infection, and cytokine use in animal models.