HEMATOPOIETIC CYTOKINES EFFECT ON A MODEL OF AIDS

说明(改编自申请人的摘要)贫血， 粒细胞减少症、淋巴细胞减少症和血小板减少症在HIV患者中很常见 感染，虽然他们的发病机制还不是很清楚。骨髓 增殖不足(无效的造血)很可能是主要的 导致这些血液学异常的原因，可能是 由于干细胞感染或基质细胞感染导致的 良好的微环境支持骨髓生长。这 生长是一个复杂的过程，需要初级和次级群体 刺激因子、营养素和细胞：细胞接触。此外, 如果是最佳的，则不能存在毒性、抑制和免疫因素 预计会有造血功能。在对感染SIV的恒河猴的研究中， 我们描述了外周血细胞减少症、分期相关的CFU-GM和 BFU-E低增殖，CD34祖细胞无感染， 大剂量IL-3和GM-CSF部分恢复CFU生长， 以及HIV分泌的抑制物或恒河猴骨髓的存在 感染H9细胞。这些数据显示了感染SIV病毒的相似性 猴子对感染艾滋病毒的人类来说，暗示着无效的造血， 有细胞动力学和可能的抑制性异常，是一个因素 支持使用该模型来研究细胞因子的作用 行政管理。在此，调查人员提出了一项全面的研究 外源性细胞因子对血液学和病毒学的影响 实验感染SIV的恒河猴给药。 该模型是有利的，因为I(1)允许对动物进行测试(没有 随之而来的抗病毒治疗)，(2)让调查人员知道 感染时间，(3)有明确的疾病进展 授权期，以及(4)初步数据支持，表明 SIV感染的血液学后果与 那些关于艾滋病毒的。具体地说，研究人员建议研究影响 外源性细胞因子对造血室的影响 扩展、细胞感染部位、病毒复制和负担 在细胞因子注射后。调查人员将利用 在感染了A型流感病毒的猴子身上测试的隔室特异性细胞因子 SIV株以淋巴细胞或单核细胞为主。预计， 通过这些目的，细胞因子在SIV感染中的积极作用 可以证明猕猴，任何细胞因子对病毒的不良影响 复制可以被阐明，模型可以被表征为 未来的细胞因子、骨髓运输和基因治疗 实验。在此提出的研究将需要努力 一组调查人员之前有过广泛的合作， 在造血学、免疫学和医学领域的经验和专业知识 SIV感染的病毒学方面，以及细胞因子在动物模型中的应用。

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.