Mutational studies of human immunodeficiency virus type 1 reverse transcriptase: The involvement of residues 183 and 184 in the fidelity of DNA synthesis
Mutational studies of human immunodeficiency virus type 1 reverse transcriptase: The involvement of residues 183 and 184 in the fidelity of DNA synthesis
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DOI：
10.1016/0014-5793(96)00747-8
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发表时间：
1996-08-12
期刊：
影响因子：
3.5
通讯作者：
Hizi, A
中科院分区：
文献类型：
--
作者：
Bakhanashvili, M;Avidan, O;Hizi, A
人类免疫缺陷病毒1型逆转录酶（HIV-1 RT）的高错误率特征是阻碍获得性免疫缺陷综合征（AIDS）预防和治疗的病毒高易变性的一个推定来源。我们通过对DNA合成的准确性进行比较研究，分析了两种HIV-1 RT突变体。每个突变体在高度保守的DNA聚合酶活性位点185位和186位的两个天门氨酸残基附近都有一个氨基酸取代，第一个突变体Met 184 -> Leu （M184L）的错插入和错配扩展都明显减少，表明DNA合成的保真度明显高于野生型HIV-1 RT。显示错配延伸减少，但错配无明显变化。因此，DNA合成的总体错误倾向模式是：野生型HIV-1 RT > Y183F > M184L。综合考虑，残基183和184可能导致HIV-1、HIV-2和其他慢病毒逆转录酶的DNA合成特征的低保真度。我们的观察结果可能与艾滋病化疗中使用的核苷类似物耐药的潜在突变的性质有关。
The high error rates characteristic of human immunodeficiency virus type-1 reverse transcriptase (HIV-1 RT) are a presumptive source of the viral hypermutability that impedes prevention and therapy of acquired immunodeficiency syndrome (AIDS), We have analyzed two mutants of HIV-1 RT by conducting a comparative study of the accuracy of DNA synthesis, Each mutant bears a single amino acid substitution adjacent to the two aspartic acid residues at positions 185 and 186 in the highly conserved DNA polymerase active site, The first mutant, Met 184 --> Leu (M184L), displays a marked reduction in both misinsertion and mispair extension, suggesting a fidelity of DNA synthesis significantly higher than that of the wild-type HIV-1 RT, The second mutant, Tyr 183 --> Phe (Y183F), shows a decrease in mispair extension with no significant change in misincorporation. Thus, the overall pattern of error-proneness of DNA synthesis is: wild-type HIV-1 RT > Y183F > M184L, Taken together, it is possible that residues 183 and 184 contribute to the low fidelity of DNA synthesis characteristic of the reverse transcriptases of HIV-1, HIV-2 and possibly, of other lentiviruses, Our observations may bear on the nature of potential mutations responsible for resistance to the nucleoside analogs used in chemotherapy of AIDS.