Drug-induced reactivation of apoptosis abrogates HIV-1 infection.
Drug-induced reactivation of apoptosis abrogates HIV-1 infection.
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DOI：
10.1371/journal.pone.0074414
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Mathews MB
中科院分区：
文献类型：
--
作者：
Hanauske-Abel HM;Saxena D;Palumbo PE;Hanauske AR;Luchessi AD;Cambiaghi TD;Hoque M;Spino M;D'Alliessi Gandolfi D;Heller DS;Singh S;Park MH;Cracchiolo BM;Tricta F;Connelly J;Popowicz AM;Cone RA;Holland B;Pe'ery T;Mathews MB
HIV-1阻断细胞凋亡，程序性细胞死亡，细胞对病毒入侵的先天防御。然而，细胞凋亡可以通过干扰HIV-1基因表达的化学试剂在HIV感染的细胞中选择性地重新激活。我们研究了两种全球使用的药物，局部抗真菌剂环吡酮和铁螯合剂去铁酮，它们对HIV感染的H9细胞和感染临床HIV-1分离株的外周血单核细胞凋亡的影响。这两种药物在HIV感染的细胞中优先激活凋亡，这表明药物介导逃避病毒对防御性凋亡的抑制。在感染的H9细胞中，环吡酮和去铁酮增强线粒体膜去极化，启动凋亡的内在途径，以执行，证明了半胱天冬酶-3激活，聚（ADP-核糖）聚合酶蛋白水解，DNA降解，和凋亡细胞形态。在分离感染的外周血单核细胞中，环吡酮使HIV-1的产生降低到病毒蛋白和RNA检测的极限。尽管长期单药治疗，环吡酮没有引起突破。即使在停药后12周也未观察到病毒重新出现，表明前病毒储库消除。在小鼠中预测对人上皮细胞的细胞毒性的试验在环吡酮浓度超过引起感染细胞死亡的浓度几个数量级时没有检测到组织损伤或细胞凋亡的激活。我们推断，环吡酮和去铁酮通过治疗性回收HIV感染细胞的凋亡能力（TRAP）发挥作用，并触发其优先消除。病毒蛋白表达的扰动表明，这两种药物的抗逆转录病毒活性源于它们抑制细胞凋亡和病毒感染所必需的细胞蛋白的羟基化的能力，例如eIF 5A。我们的研究结果确定环吡酮和去铁酮作为选择性杀细胞抗病毒药物的原型，通过破坏受感染的细胞来消除病毒感染。一个基于药物的药物发现计划，基于这些化合物，是必要的，以确定这些药物在HIV感染患者的临床试验的潜力。
HIV-1 blocks apoptosis, programmed cell death, an innate defense of cells against viral invasion. However, apoptosis can be selectively reactivated in HIV-infected cells by chemical agents that interfere with HIV-1 gene expression. We studied two globally used medicines, the topical antifungal ciclopirox and the iron chelator deferiprone, for their effect on apoptosis in HIV-infected H9 cells and in peripheral blood mononuclear cells infected with clinical HIV-1 isolates. Both medicines activated apoptosis preferentially in HIV-infected cells, suggesting that the drugs mediate escape from the viral suppression of defensive apoptosis. In infected H9 cells, ciclopirox and deferiprone enhanced mitochondrial membrane depolarization, initiating the intrinsic pathway of apoptosis to execution, as evidenced by caspase-3 activation, poly(ADP-ribose) polymerase proteolysis, DNA degradation, and apoptotic cell morphology. In isolate-infected peripheral blood mononuclear cells, ciclopirox collapsed HIV-1 production to the limit of viral protein and RNA detection. Despite prolonged monotherapy, ciclopirox did not elicit breakthrough. No viral re-emergence was observed even 12 weeks after drug cessation, suggesting elimination of the proviral reservoir. Tests in mice predictive for cytotoxicity to human epithelia did not detect tissue damage or activation of apoptosis at a ciclopirox concentration that exceeded by orders of magnitude the concentration causing death of infected cells. We infer that ciclopirox and deferiprone act via therapeutic reclamation of apoptotic proficiency (TRAP) in HIV-infected cells and trigger their preferential elimination. Perturbations in viral protein expression suggest that the antiretroviral activity of both drugs stems from their ability to inhibit hydroxylation of cellular proteins essential for apoptosis and for viral infection, exemplified by eIF5A. Our findings identify ciclopirox and deferiprone as prototypes of selectively cytocidal antivirals that eliminate viral infection by destroying infected cells. A drug-based drug discovery program, based on these compounds, is warranted to determine the potential of such agents in clinical trials of HIV-infected patients.
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