PROGRAMMED CELL-DEATH IN AIDS-RELATED HIV AND SIV INFECTIONS
PROGRAMMED CELL-DEATH IN AIDS-RELATED HIV AND SIV INFECTIONS
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DOI：
10.1089/aid.1993.9.553
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发表时间：
1993-06-01
影响因子：
1.5
通讯作者：
MONTAGNIER, L
中科院分区：
文献类型：
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作者：
GOUGEON, ML;GARCIA, S;MONTAGNIER, L
了解人类免疫缺陷病毒 (HIV) 感染的复杂病理学的困难之一是解释 CD4 辅助 T 细胞群的逐渐耗竭以及由此导致的免疫系统的破坏。尽管在体外观察到了 HIV 的细胞病变效应，但它们不能在体内解释 CD4 T 细胞的耗竭，因为相对较少的细胞被有效感染。因此必须设想免疫机制。我们发现，无症状 HIV 感染者的外周血淋巴细胞 (PBL) 已准备好进行自杀过程，称为细胞凋亡或程序性细胞死亡 (PCD)。用离子霉素刺激淋巴细胞可增强细胞凋亡的 DNA 断裂特征，离子霉素是适当引发的细胞中已知的细胞凋亡诱导剂。对编程为凋亡的 T 细胞亚群的鉴定表明，在没有刺激的情况下培养或用离子霉素进行多克隆刺激时，CD4+ 和 CD8+ 细胞都会死亡。在用自身 MHC II 类依赖性超抗原（即来自葡萄球菌 (SEB)、链球菌 (ETA) 和细菌毒素）刺激后，也观察到激活诱导的细胞死亡。 支原体 (MAM) 以及在这些条件下 CD4+ T 细胞优先受到影响。为了探讨细胞凋亡是否需要新的大分子合成，测试了各种已知的细胞凋亡抑制剂，如放线菌酮、环孢菌素 A、Zn2+ 或 EGTA。发现激活诱导的细胞凋亡对这些抑制剂敏感，表明存在活性机制，但在未刺激的培养物中观察到的细胞凋亡则不然，这表明这些细胞已经包含完整的死亡机制。细胞因子混合物存在时可以预防细胞凋亡，这种预防所需的最小信号是 IL-1α 和 IL-2。最后，IL-1α 和 IL-2 之间的相关性 通过比较慢病毒感染的灵长类动物对艾滋病敏感（SIV 感染的猕猴）和耐药（HIV 感染的黑猩猩）的淋巴细胞，提示了 PCD 和 AIDS 的发病机制。总而言之，我们的结果表明，在 HIV 或 SIV 感染期间，PCD 可能有助于体内抗原刺激后反应性 T 细胞的缺失。
One of the difficulties in understanding the complex pathology of human immunodeficiency virus (HIV) infection is to explain the progressive depletion of the CD4 helper T cell population and consequently the destruction of the immune system. Although cytopathic effects of HIV are observed in vitro, they cannot in vivo account for CD4 T cell depletion because relatively few cells are productively infected. Thus immunological mechanisms must be envisaged. We have found that peripheral blood lymphocytes (PBLs) from asymptomatic HIV-infected individuals are primed for a suicide process known as apoptosis or programmed cell death (PCD). DNA fragmentation characteristic of apoptosis was enhanced by stimulation of lymphocytes with ionomycin, a known inducer of apoptosis in suitably primed cells. Identification of the T cell subpopulations programmed for apoptosis indicated that both CD4+ and CD8+ cells died when cultured without stimulation or when polyclonally stimulated with ionomycin.Activation-induced cell death was also observed after stimulation with self-MHC class II-dependent superantigens, namely bacterial toxins from Staphylococcus (SEB), Streptococcus (ETA), and Myocoplasma (MAM) and under these conditions the CD4+ T cells were preferentially affected. To explore whether new macromolecular synthesis were required for apoptosis, various known inhibitors of apoptosis such as cycloheximide, cyclosporin A, Zn2+, or EGTA were tested. Activation-induced apoptosis was found sensitive to these inhibitors, indicating an active mechanism, but apoptosis observed in nonstimulated cultures was not, suggesting that these cells already contained the complete machinery for death.Prevention of apoptosis could be obtained in the presence of a mixture of cytokines and the minimal signal necessary for this prevention was IL-1alpha and IL-2.Finally, a correlation between PCD and AIDS pathogenesis was suggested by the comparison of lymphocytes from lentivirus-infected primates suceptible (SIV-infected macaques) and resistant (HIV-infected chimpanzees) to AIDS. Altogether our results suggest that, during HIV or SIV infection, PCD may contribute in vivo to the deletion of reactive T cells after antigenic stimulation.