Ciccosanti Fabiola, Corazzari Marco, Soldani Fabio, Matarrese Paola, Pagliarini Vittoria, Iadevaia Valentina, Tinari Antonella, Zaccarelli Mauro, Perfettini Jean-Luc, Malorni Walter, Kroemer Guido, Antinori Andrea, Fimia Gian Maria, Piacentini Mauro
National Institute for Infectious Diseases, 'Lazzaro Spallanzani' IRCCS, Rome, Italy.
Antivir Ther. 2010;15(3):377-90. doi: 10.3851/IMP1530.
Highly active antiretroviral therapy (HAART) has largely reduced the occurrence of AIDS-related diseases and death in HIV-infected patients. However, HAART produces serious side effects mainly attributed to mitochondrial toxicity.
To elucidate the molecular basis of HAART-related dysfunctions, we analysed the mitochondrial proteome of peripheral blood mononuclear cells from HIV-infected patients using two-dimensional gel electrophoresis and MALDI-TOF/TOF mass spectrometry. Proteomic analysis was performed on HIV patients who were either treatment-naive or under HAART therapy including zidovudine or stavudine as nucleoside reverse transcriptase inhibitors (NRTIs).
As compared to healthy donors, HAART-treated HIV-infected patients exhibited decreased levels of mitochondrial enzymes associated with energy production as well as mitochondrial chaperones. Moreover, significant alterations in the mitochondria-cytoskeleton network were observed. Notably, most of these changes were already detectable in untreated HIV carriers and persisted or worsened after HAART, indicating that relevant mitochondrial alterations were initially caused by HIV infection. Finally, in vitro experiments aimed at validating the proteomic results showed that down-regulation of the mitochondrial chaperone prohibitin is a causative event in NRTI-induced mitochondrial damage.
Our results indicate a major role of HIV infection in the mitochondrial toxicity of HAART-treated patients and identify novel candidate markers for assessing the risk of HIV- and HAART-related pathologies.
高效抗逆转录病毒疗法（HAART）已在很大程度上降低了HIV感染患者中与艾滋病相关疾病的发生率和死亡率。然而，HAART会产生严重的副作用，主要归因于线粒体毒性。
为了阐明HAART相关功能障碍的分子基础，我们使用二维凝胶电泳和基质辅助激光解吸电离飞行时间串联质谱（MALDI-TOF/TOF MS）分析了HIV感染患者外周血单个核细胞的线粒体蛋白质组。对未接受过治疗或正在接受包括齐多夫定或司他夫定作为核苷类逆转录酶抑制剂（NRTIs）的HAART治疗的HIV患者进行了蛋白质组学分析。
与健康供体相比，接受HAART治疗的HIV感染患者与能量产生相关的线粒体酶以及线粒体伴侣蛋白水平降低。此外，观察到线粒体-细胞骨架网络有显著改变。值得注意的是，这些变化中的大多数在未治疗的HIV携带者中已经可以检测到，并且在HAART后持续存在或恶化，这表明相关的线粒体改变最初是由HIV感染引起的。最后，旨在验证蛋白质组学结果的体外实验表明，线粒体伴侣蛋白 prohibitin 的下调是NRTI诱导的线粒体损伤的致病事件。
我们的结果表明HIV感染在接受HAART治疗患者的线粒体毒性中起主要作用，并确定了用于评估HIV和HAART相关病理风险的新型候选标志物。
