The antiretrovirus drug 3'-azido-3'-deoxythymidine increases the retrovirus mutation rate.
The antiretrovirus drug 3'-azido-3'-deoxythymidine increases the retrovirus mutation rate.
复制标题
抗逆转录病毒药物3-叠氮基-3-脱氧胸苷会增加逆转录病毒突变率。
DOI：
10.1128/jvi.71.6.4254-4263.1997
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
Pathak,VK
中科院分区：
文献类型：
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作者：
Julias,JG;Kim,T;Arnold,G;Pathak,VK
先前观察到核苷类似物5-氮杂胞苷在逆转录病毒复制的一个循环中使脾坏死病毒（SNV）突变率增加13倍（V.K. Pathak和H. M. Temin，J. Virol. 66：3093-3100，1992）。基于这一观察，我们假设核苷类似物作为抗病毒药物也可能增加逆转录病毒突变率。我们试图确定3 '-叠氮基-3'-脱氧胸苷（AZT），人类免疫缺陷病毒1型（HIV-1）感染的主要治疗药物，是否会增加逆转录病毒突变率。使用两种试验来确定AZT对逆转录病毒突变率的影响。第一个试验的策略涉及测量在基于SNV和鼠白血病病毒的逆转录病毒载体的一个复制循环中lacZ基因的体内失活速率。我们观察到7倍和10倍的SNV突变频率增加后，治疗的靶细胞与0.1和0.5 μ M AZT，分别。用0.5和1.0 μ M AZT处理靶细胞后，小鼠白血病病毒突变频率分别增加了2倍和3倍。第二个试验使用含有lacZ α基因的基于SNV的穿梭载体。在大肠杆菌中回收作为质粒的前病毒，并测量lacZ α的失活速率。结果表明，靶细胞的处理使总体突变率增加了两到三倍。突变前病毒的DNA序列分析表明，AZT增加了缺失和替换率。这些结果表明，AZT治疗HIV-1感染可能会增加病毒变异的程度，并改变病毒的进化或发病机制。
It was previously observed that the nucleoside analog 5-azacytidine increased the spleen necrosis virus (SNV) mutation rate 13-fold in one cycle of retrovirus replication (V. K. Pathak and H. M. Temin, J. Virol. 66:3093-3100, 1992). Based on this observation, we hypothesized that nucleoside analogs used as antiviral drugs may also increase retrovirus mutation rates. We sought to determine if 3'-azido-3'-deoxythymidine (AZT), the primary treatment for human immunodeficiency virus type 1 (HIV-1) infection, increases the retrovirus mutation rate. Two assays were used to determine the effects of AZT on retrovirus mutation rates. The strategy of the first assay involved measuring the in vivo rate of inactivation of the lacZ gene in one replication cycle of SNV- and murine leukemia virus-based retroviral vectors. We observed 7- and 10-fold increases in the SNV mutant frequency following treatment of target cells with 0.1 and 0.5 microM AZT, respectively. The murine leukemia virus mutant frequency increased two- and threefold following treatment of target cells with 0.5 and 1.0 microM AZT, respectively. The second assay used an SNV-based shuttle vector containing the lacZ alpha gene. Proviruses were recovered as plasmids in Escherichia coli, and the rate of inactivation of lacZ alpha was measured. The results indicated that treatment of target cells increased the overall mutation rate two- to threefold. DNA sequence analysis of mutant proviruses indicated that AZT increased both the deletion and substitution rates. These results suggest that AZT treatment of HIV-1 infection may increase the degree of viral variation and alter virus evolution or pathogenesis.