Caffeine inhibits human immunodeficiency virus type 1 transduction of nondividing cells
Caffeine inhibits human immunodeficiency virus type 1 transduction of nondividing cells
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DOI：
10.1128/jvi.79.4.2058-2065.2005
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发表时间：
2005-02-01
影响因子：
5.4
通讯作者：
Pomerantz, RJ
中科院分区：
文献类型：
--
作者：
Daniel, R;Marusich, E;Pomerantz, RJ
咖啡因是DNA修复和DNA损伤激活检查点的有效抑制剂。我们最近发现，咖啡因抑制分裂细胞的逆转录病毒转导，最有可能是通过阻断整合后修复。这种作用可能至少部分地由咖啡因的细胞靶点、共济失调毛细血管扩张和Rad 3相关（ATR）激酶介导。在这项研究中，我们提出的证据表明，咖啡因也抑制非分裂细胞的有效转导。我们观察到在咖啡因处理的生长停滞细胞以及咖啡因处理的终末分化的人类神经元和巨噬细胞中的转导减少。此外，在缺乏Vpr的人类免疫缺陷病毒1型（HIV-1）载体中观察到这种缺陷，表明该效应与感染病毒体中该病毒蛋白的存在无关。最后，我们表明，HIV-1转导nocodazole逮捕的细胞减少在细胞中表达ATR显性阴性蛋白（激酶死亡ATR [ATRkd]）和剩余的转导ATRkd表达细胞是相对耐咖啡因。总之，这些数据表明，咖啡因对HIV-1转导的影响至少部分是通过抑制ATR途径介导的，但不依赖于咖啡因介导的细胞周期检查点的抑制。
Caffeine is an efficient inhibitor of DNA repair and DNA damage-activated checkpoints. We have shown recently that caffeine inhibits retroviral transduction of dividing cells, most likely by blocking postintegration repair. This effect may be mediated at least in part by a cellular target of caffeine, the ataxia telangiectasiamutated and Rad3-related (ATR) kinase. In this study, we present evidence that caffeine also inhibits efficient transduction of nondividing cells. We observed reduced transduction in caffeine-treated growth-arrested cells as well as caffeine-treated terminally differentiated human neurons and macrophages. Furthermore, this deficiency was observed with a human immunodeficiency virus type 1 (HIV-1) vector lacking Vpr, indicating that the effect is independent of the presence of this viral protein in the infecting virion. Finally, we show that HIV-1 transduction of nocodazole-arrested cells is reduced in cells that express an ATR dominant-negative protein (kinase-dead ATR [ATRkd]) and that the residual transduction of ATRkd-expressing cells is relatively resistant to caffeine. Taken together, these data suggest that the effect(s) of caffeine on HIV-1 transduction is mediated at least partly by the inhibition of the ATR pathway but is not dependent on the caffeine-mediated inhibition of cell cycle checkpoints.