PRECLINICAL ANIMAL MODEL TO ASSESS THE SAFETY OF RETROVIRALLY RESISTANT CELLS

HIV感染者对逆转录病毒耐药细胞的管理 正在积极研究中。利用获得性免疫缺陷小鼠模型 在逆转录病毒诱导下，我们探讨了黄连的安全性和有效性。 敏感宿主动物体内的抗逆转录病毒细胞。两种不同的 建立了1个亲本品系的别苯小鼠品系。 是敏感的，另一种对小鼠逆转录病毒具有抵抗力。 重要的是，逆转录病毒的耐药机制在两种耐药中 压力伙伴的情况有所不同。单个动物的淋巴嵌合体 用流式细胞仪技术和随后的动物进行评估 接种逆转录病毒混合物。对这些动物进行了时间评估 到淋巴结病，死亡时间，流式细胞仪参数的变化， 并用于逆转录病毒物种的恢复。尽管存在差异，但 逆转录病毒耐药机制，存在实质性，但较少 比大多数抗性细胞不能提供任何保护 抵抗疾病，动物患上淋巴结病并死于 与完全敏感的对照组小鼠相同的时间框架或更快的速度 与逆转录病毒物种的恢复率相当。然而，在多个 主要淋巴种群具有抵抗力的动物 基因，这些动物没有患上疾病，而且有明显的 逆转录病毒水平的降低。重要的是，易感人群的命运 细胞根据抗病机制的不同而不同， 易感淋巴细胞室显著减少 组合在一起，但另一个没有变化。因此，很明显，在那里 是敏感和耐药淋巴细胞之间的关键平衡 这决定了动物是死于疾病，还是活了很长时间 长期抗性，而耐药性的机制可能决定 易感细胞群体的命运。该模型还解决了 与感染性逆转录病毒嗜性变化有关的问题 内源性逆转录病毒，存在于供体细胞的基因组中。 已经计划进行更多的研究，以确定关键的抗性 负责提供保护作用的细胞种群 用于测试其注入逆转录病毒感染后的安全性 动物，以及评估病毒嗜性的变化。 Sechler，JMG，Lawler，A.，Hartley，JW，Morse，HC，III和Rosenberg，As. 敏感品系在四氯苯型小鼠体内诱导女佣的研究 并且对疾病有抵抗力。手稿正在准备中。

Administration of retrovirally resistant cells to HIV infected humans is under active study. Using a murine model of acquired immunodeficiency induced by retroviruses, we explored the safety and efficacy of retrovirally resistant cells in a susceptible host animal. Two different strains of allophenic mice were constructed, in which one parent strain was susceptible and the other resistant to murine retroviruses. Importantly, the mechanism of retroviral resistance in the two resistant strain partners differed. Lymphoid chimerism of individual animals was assessed by flow cytometric techniques and the animals subsequently inoculated with the retroviral mix. The animals were assessed for time to lymphadenopathy, time to death, changes in flow cytometric parameters, and for recovery of retroviral species. Despite differences in mechanism of retroviral resistance, the presence of substantial, but less than predominant numbers of resistant cells afforded no protection against disease, with animals developing lymphadenopathy and dying in the same time frame or more rapidly than fully susceptible control mice and with comparable recovery of retroviral species. However, in multiple animals in which the predominant lymphoid population was of the resistant genotype, the animals failed to develop disease, and there was a marked reduction in level of retrovirus. Importantly, the fate of susceptible cells differed depending on the mechanism of disease resistance, with a marked reduction in the susceptible lymphoid cell compartment in one combination but no change in the other. Thus, it is apparent that there is a critical balance between susceptible and resistant lymphoid cells that determines whether the animals succumb to disease, or achieve long term resistance, and that the mechanism of resistance may determine the fate of the susceptible cell population. This model also addresses issues pertaining to changes in tropism of the infective retrovirus and of endogenous retroviruses, present in the genome of donor cells. Additional studies have been planned to identify the critical resistant cellular populations responsible for conferring protection against disease, for testing their safety when infused into retrovirally infected animals, and for assessing changes in viral tropism. Sechler, JMG, Lawler, A., Hartley, JW, Morse, HC,III, and Rosenberg, AS. Induction of MAIDS in Allophenic Mice Generated from Strains Susceptible and Resistant to Disease. Manuscript in Preparation.