MECHANISM OF IMMUNOTOXICITY OF THE AIDS THERAPEUTICS DDC AND D4T

2‘，3’-双脱氧核苷是唯一被批准的治疗方法 减缓人类免疫缺陷病毒的发展 (HIV)，已知会导致获得性免疫缺陷综合征 (艾滋病)。越来越多的证据表明，这些内源性的类似物 DNA复制的前体具有潜在的毒性 几个器官。这个实验室以前的研究表明 循环中的CD4+淋巴样细胞显著减少 非人灵长类物种恒河猴的淋巴细胞池。 这项拟议的研究的目的是阐明 核苷类似物ddi和d4T对免疫的毒性 在细胞水平上的系统。我们的假设是核苷 在特定的淋巴细胞亚群中引起延迟的细胞毒性， 即CD4+辅助性T细胞。已知双脱氧核苷 扰乱正常的线粒体生物发生，我们建议 毒性是由线粒体功能障碍介导的。 增殖的淋巴细胞。线粒体活性不足 可能导致三磷酸腺苷的降低和细胞死亡的加强 或淋巴细胞的周转。这种情况可能是一种解释 对于我们在之前观察到的CD4+细胞的减少 在接触了ddC和ddi的非人类灵长类动物中进行的实验。 为了实现这一目标，我们首先提出了测量移位或 CD_4细胞表面表达淋巴细胞数量的变化 正常和β2-微球蛋白基因中的标记失活， 转基因小鼠。我们将观察核苷的直接作用 这些转基因动物体内的CD4+细胞。第二，我们建议 描述免疫反应性的任何变化 核苷暴露可能诱导的淋巴细胞。最后， 我们建议评估体内暴露于ddC和d4T的影响 淋巴细胞线粒体功能的研究 测定对线粒体特异性酶的影响 细胞色素氧化酶。我们认为这些方法将引出重要的 可以应用于这些管理的信息 HIV血清阳性和艾滋病患者的药物。

The 2',3'-dideoxynucleosides are the only approved therapeutics for slowing of the progression of the human immunodeficiency virus (HIV) which is known to cause acquired immunodeficiency syndrome (AIDS). There is mounting evidence that these analogs of endogenous precursors for DNA replication are potentially toxic towards several organs. Previous studies in this laboratory have indicated that CD4+ lymphoid cells significantly decreased in the circulating pool of lymphocytes in the nonhuman primate species, rhesus monkey. The goal of this proposed research is to elucidate the mechanism of toxicity of the nucleoside analogs, ddI and d4T towards the immune system at the cellular level. Our hypothesis is that nucleosides cause a delayed cytotoxicity in specific lymphocyte subpopulations, namely CD4+ helper T cells. It is known that dideoxynucleosides disrupt normal mitochondrial biogenesis and we propose that toxicity is mediated by dysfunction of the mitochondria in proliferating lymphocytes. A deficit in mitochondrial activity could result in a lowering of ATP and the enhancement of cell death or turnover of lymphocytes. This scenario could be one explanation for the observed decrease of CD4+ cells we observed in previous experiments in nonhuman primates that were exposed to ddC and ddI. To accomplish the goal, we first propose to measure shifts or changes in the number of lymphocytes expressing the CD4 surface marker in normal and beta2-microglobulin gene inactivated, transgenic mice. We will observe the direct effect of nucleosides on CD4+ cells in these transgenic animals. Secondly, we propose to characterize any changes in the immune responsiveness of lymphocytes which may be induced by nucleoside exposure. Finally, we propose to assess the effect of in vivo exposure to ddC and d4T on the functional capacity of lymphoid cell mitochondria by measuring the effect on the mitochondrial specific enzyme cytochrome oxidase. We feel these approaches will elicit important information which can be applied to the administration of these drugs in HIV seropositive and AIDS patients.