The HIV Protease Inhibitors Nelfinavir and Saquinavir, but Not a Variety of HIV Reverse Transcriptase Inhibitors, Adversely Affect Human Proteasome Function
The HIV Protease Inhibitors Nelfinavir and Saquinavir, but Not a Variety of HIV Reverse Transcriptase Inhibitors, Adversely Affect Human Proteasome Function
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DOI：
10.1177/135965350501000203
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发表时间：
2005-02
影响因子：
1.2
通讯作者：
M. Piccinini;M. T. Rinaudo;A. Anselmino;B. Buccinnà;C. Ramondetti;A. Dematteis;E. Ricotti;L. Palmisano-L.
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文献类型：
--
作者：
M. Piccinini;M. T. Rinaudo;A. Anselmino;B. Buccinnà;C. Ramondetti;A. Dematteis;E. Ricotti;L. Palmisano-L.
背景在HIV感染患者中，抗逆转录病毒治疗（通常包括HIV蛋白酶抑制剂（PI）和逆转录酶抑制剂（RTI）的组合）的一些临床和免疫学益处不能仅通过药物对病毒酶的作用来解释。蛋白酶体构成了泛素ATP依赖性途径的中心蛋白酶，参与许多细胞过程，以及HIV成熟和侵袭性。目的：探讨PI奈非那韦和沙奎那韦以及RTI阿巴卡韦、奈韦拉平、地拉韦啶、司他夫定和去羟肌苷在体外和体内是否影响蛋白酶体功能。方法用纯化的人26 S和20 S蛋白酶体在不同浓度药物作用下测定肽酶活性。细胞内蛋白酶体的蛋白水解活性进行了评估，通过寻找泛素标记的蛋白质在HL 60细胞孵育和无药物。结果在治疗剂量下，奈非那韦和沙奎那韦抑制蛋白酶体肽酶活性，并引起细胞内聚泛素化蛋白的积累，这是体内蛋白酶体蛋白水解抑制的标志; RTIs未能引起任何效果。结论两种PI均以蛋白酶体为靶点，而RTI则不以蛋白酶体为靶点。因此，在HIV感染的患者中，包括两种PI之一的治疗的有益效果应部分依赖于抑制宿主蛋白酶体功能。
Background In HIV-infected patients some clinical and immunological benefits of antiretroviral therapy, which frequently include a combination of HIV protease inhibitors (PIs) and reverse transcriptase inhibitors (RTIs), cannot be solely explained by the drugs’ action on viral enzymes. Proteasomes constitute the central protease of the ubiquitin ATP-dependent pathway involved in many cellular processes, as well as in HIV maturation and aggressiveness. Objective: To explore whether the PIs nelfinavir and saquinavir and the RTIs abacavir, nevirapine, delavirdine, stavudine and didanosine affect proteasome function in vitro and in vivo. Methods Peptidase activity of purified human 26S and 20S proteasomes was assayed with and without the drugs at different concentrations. Intracellular proteasome proteolytic activity was evaluated by searching for ubiquitin-tagged proteins in HL60 cells incubated with and without the drugs. Results At therapeutic dosages, nelfinavir and saquinavir inhibited proteasome peptidase activity and caused intracellular accumulation of polyubiquitinated proteins, a hallmark of proteasome proteolytic inhibition in vivo; the RTIs failed to evoke either effect. Conclusion Proteasomes are targeted by the two PIs but not the RTIs. Therefore, in HIV-infected patients the beneficial effect of a therapy including one of the two PIs should partly rely on inhibition of host proteasome function.