SAMHD1 enhances nucleoside-analogue efficacy against HIV-1 in myeloid cells
SAMHD1 enhances nucleoside-analogue efficacy against HIV-1 in myeloid cells
复制标题
SAMHD1 增强髓样细胞中核苷类似物对抗 HIV-1 的功效
作者：
P. Ordonez;S. Kunzelmann;Harriet C. T. Groom;M. Yap;Simon Weising;C. Meier;K. Bishop;I. Taylor;J. Stoye
SAMHD1是一种胞内酶，能特异性地将脱氧核苷三磷酸降解为组分核苷和无机三磷酸。在髓系来源的树突状细胞、巨噬细胞以及静息T细胞中，SAMHD1通过这种dNTP三磷酸水解酶活性将细胞dNTP池减少到不能支持生产性逆转录的水平，从而阻止HIV-1感染。我们现在证明，除了对病毒复制的这种直接影响外，操纵细胞SAMHD1的活性可以显著增强或降低核苷酸类似物反转录抑制剂的抗HIV-1效果，这可能是由于调节了竞争病毒聚合酶招募的dNTP池的结果。此外，各种通常不被认为是抗逆转录病毒药物的其他基于核苷酸的类似物，如抗疱疹药物阿昔洛韦和更昔洛韦以及抗癌药物氯法拉滨，现在被证明是在低dNTPs条件下有效的抗HIV-1药物。这反过来又暗示了核苷酸类似物在低dNTPs水平的分化细胞中抑制HIV-1的新用途。
SAMHD1 is an intracellular enzyme that specifically degrades deoxynucleoside triphosphates into component nucleoside and inorganic triphosphate. In myeloid-derived dendritic cells and macrophages as well as resting T-cells, SAMHD1 blocks HIV-1 infection through this dNTP triphosphohydrolase activity by reducing the cellular dNTP pool to a level that cannot support productive reverse transcription. We now show that, in addition to this direct effect on virus replication, manipulating cellular SAMHD1 activity can significantly enhance or decrease the anti-HIV-1 efficacy of nucleotide analogue reverse transcription inhibitors presumably as a result of modulating dNTP pools that compete for recruitment by viral polymerases. Further, a variety of other nucleotide-based analogues, not normally considered antiretrovirals, such as the anti-herpes drugs Aciclovir and Ganciclovir and the anti-cancer drug Clofarabine are now revealed as potent anti-HIV-1 agents, under conditions of low dNTPs. This in turn suggests novel uses for nucleotide analogues to inhibit HIV-1 in differentiated cells low in dNTPs.
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