Bucur S Z, Lackey D A, Adams J W, Lee M E, Villinger F, Mayne A, Bray R A, Winton E F, Novembre F, Strobert E A, De Rosayro J, Dailey P J, Ansari A A, Hillyer C D
Department of Pathology, Emory University, Atlanta, Georgia 30322, USA.
AIDS Res Hum Retroviruses. 1998 May 20;14(8):651-60. doi: 10.1089/aid.1998.14.651.
The hematologic abnormalities of SIV and HIV are well described, although the mechanisms that lead to hematopoietic dysfunction are yet to be fully defined. A number of growth factors and cytokines have been used to induce the differentiation, maturation, and proliferation of appropriate lineages, with the aim that such therapy will lead to functional hematopoietic reconstitution. Within this context, some cytokines have been shown to influence HIV and SIV replication in vitro and, in selected cases, in vivo. However, few studies detail the effects of hematopoietic cytokines such as IL-3, Flt-3 ligand, G-CSF, Tpo, and Epo or correlate the effects on virus replication. In an effort to address this issue, we infected 12 rhesus macaques with 500 TCID50 of SIVmac239 and intensively evaluated hematologic, virologic, and immunologic parameters during administration of cytokines. When all animals had lymphadenopathy, hepatosplenomegaly, and CD4+ cell counts > or =1000/microl, subgroups of three rhesus macaques were administered either rhFlt-3; rrIL-3a; combination of rhG-CSF, rhTpo, and rhEpo (rhGET); or rrIL-12. Fourteen days of rhFlt-3 administration induced expansion of the bone marrow CD34+ cells and granulocyte-macrophage colony-forming units (GM-CFUs) and increased absolute peripheral blood CD34+ cells and total CFUs. Following rrIL-3 and rhGET administration absolute peripheral blood CD34+ cells and total CFUs increased. rhGET also increased granulocyte, platelet, and reticulocyte counts by day 14 of administration. Branched DNA and coculture assays did not demonstrate any significant change in viral load with any of the cytokines administered. These data suggest that SIV-infected rhesus macaques have the hematopoietic capability to expand and mobilize CD34+ and GM-CFU progenitors and formed elements at 6-8 months postinfection in response to various cytokines, without increasing viral load.
虽然导致造血功能障碍的机制尚未完全明确，但猴免疫缺陷病毒（SIV）和人类免疫缺陷病毒（HIV）的血液学异常已有详尽描述。许多生长因子和细胞因子已被用于诱导合适谱系的分化、成熟和增殖，目的是使这种治疗能够导致功能性造血重建。在此背景下，一些细胞因子已被证明在体外以及在某些特定情况下在体内会影响HIV和SIV的复制。然而，很少有研究详细描述造血细胞因子如白细胞介素-3（IL-3）、Flt-3配体、粒细胞集落刺激因子（G-CSF）、血小板生成素（Tpo）和促红细胞生成素（Epo）的作用，或者将这些作用与病毒复制相关联。为了解决这个问题，我们用500个组织培养感染剂量50（TCID50）的猴免疫缺陷病毒（SIVmac239）感染了12只恒河猴，并在给予细胞因子期间对血液学、病毒学和免疫学参数进行了深入评估。当所有动物出现淋巴结病、肝脾肿大且CD4 + 细胞计数≥1000/微升时，将三只恒河猴分为一组，分别给予重组人Flt-3（rhFlt-3）；重组恒河猴IL-3a（rrIL-3a）；重组人G-CSF、重组人Tpo和重组人Epo的组合（rhGET）；或重组恒河猴IL-12。给予rhFlt-3 14天可诱导骨髓CD34 + 细胞和粒细胞 - 巨噬细胞集落形成单位（GM-CFU）扩增，并增加外周血绝对CD34 + 细胞和总CFU数量。给予rrIL-3和rhGET后，外周血绝对CD34 + 细胞和总CFU数量增加。到给药第14天时，rhGET还增加了粒细胞、血小板和网织红细胞计数。分支DNA和共培养试验未显示给予任何一种细胞因子后病毒载量有任何显著变化。这些数据表明，感染SIV的恒河猴在感染后6 - 8个月具有造血能力，能够在各种细胞因子的作用下扩增和动员CD34 + 和GM-CFU祖细胞以及成熟血细胞，而不会增加病毒载量。
