Inhibition of activation-induced programmed cell death and restoration of defective immune responses of HIV+ donors by cysteine protease inhibitors.
Inhibition of activation-induced programmed cell death and restoration of defective immune responses of HIV+ donors by cysteine protease inhibitors.
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半胱氨酸蛋白酶抑制剂抑制激活诱导的程序性细胞死亡并恢复 HIV 供体有缺陷的免疫反应。
DOI：
10.4049/jimmunol.153.2.862
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发表时间：
1994
影响因子：
4.4
通讯作者：
P. Henkart
中科院分区：
文献类型：
--
作者：
A. Sarin;M. Clerici;S. Blatt;C. Hendrix;G. Shearer;P. Henkart
在95名HIV+献血者中，有58人在体外激活HIV+献血者的PBL后2天内发生了程序性细胞死亡(PCD)，相比之下，30名对照HIV献血者中只有2人发生了程序性细胞死亡。来自HIV+捐献者的CD4+和CD8+T细胞在这些条件下死亡，这些细胞表现出凋亡的核形态和DNA片段化。为了验证这种细胞死亡与TCR在正常分裂的T细胞中诱导的死亡具有共同的生化途径这一假设，我们测试了钙激活的半胱氨酸蛋白酶Calain的抑制剂对HIV+捐赠者激活诱导的PCD的阻断能力。E-(环氧琥珀酰基)类半胱氨酸蛋白酶抑制剂对HIV+PCD反应的抑制率为40%~60%，而乙醛抑制剂亮肽素和钙蛋白酶抑制剂II的抑制率为60%~67%。通过检测Calain抑制剂对HIV+捐献者有缺陷的Ag和丝裂原依赖的增殖反应的影响，来检验这种依赖于Calain的死亡途径在HIV诱导的功能性T辅助细胞缺陷中的作用。在这些缺陷反应中，有20%到50%被钙蛋白酶抑制剂显著恢复到正常水平，而正常捐赠者的对照反应基本上没有受到影响。这些数据表明，依赖于钙蛋白酶的PCD途径有助于艾滋病毒相关的免疫缺陷，并表明使用钙蛋白酶抑制剂作为治疗艾滋病毒感染的一种可能途径。
In vitro activation of PBLs from HIV+ individuals resulted in programmed cell death (PCD) within 2 days in 58 of 95 HIV+ blood donors, in contrast to only two of 30 control HIV- donors. CD4+ and CD8+ T cells from HIV+ donors died under these conditions, and these cells showed apoptotic nuclear morphology and DNA fragmentation. To test the hypothesis that this cell death shares a common biochemical pathway with that induced by TCR cross-linking in normal dividing T cells, inhibitors of the calcium-activated cysteine protease calpain were tested for their ability to block the activation-induced PCD of HIV+ donors. The E-64 (epoxysuccinyl) class of cysteine protease inhibitors gave 40% to 60% inhibition of HIV+ PCD responses, while the aldehyde inhibitors, leupeptin and calpain inhibitor II, gave 60% to 67% inhibition. The involvement of this calpain-dependent death pathway in HIV-induced functional T helper cell deficiency was tested by examining the effect of calpain inhibitors on the defective Ag- and mitogen-dependent proliferative responses of HIV+ donors. Twenty to fifty percent of such defective responses were significantly restored toward normal levels by calpain inhibitors, whereas control responses by normal donors were largely unaffected. These data suggest that a calpain-dependent PCD pathway contributes to HIV-associated immunodeficiency and suggest the use of calpain inhibitors as a possible route to therapy of HIV infection.