Correlation of Phenotypic Zidovudine Resistance with Mutational Patterns in the Reverse Transcriptase of Human Immunodeficiency Virus Type 1: Interpretation of Established Mutations and Characterization of New Polymorphisms at Codons 208, 211, and 214
Correlation of Phenotypic Zidovudine Resistance with Mutational Patterns in the Reverse Transcriptase of Human Immunodeficiency Virus Type 1: Interpretation of Established Mutations and Characterization of New Polymorphisms at Codons 208, 211, and 214
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表型齐多夫定耐药性与 1 型人类免疫缺陷病毒逆转录酶突变模式的相关性：密码子 208、211 和 214 处已确定突变的解释和新多态性的表征
DOI：
10.1128/aac.47.1.54-61.2003
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发表时间：
2003
影响因子：
4.9
通讯作者：
K. Hertogs
中科院分区：
文献类型：
--
作者：
M. Stürmer;S. Staszewski;H. Doerr;B. Larder;S. Bloor;K. Hertogs
齐多夫定耐药（ZDV-R）与人类免疫缺陷病毒1型（HIV-1）逆转录酶（RT）基因密码子41、67、70、210、215和219处的典型基因型改变以及多核苷耐药（MNR）复合物（Q151 M MNR复合物; 6-bp插入/A62 V复合物）有关。此外，在经典ZDV突变加上M184 V突变的背景下，对ZDV的抗性增强与位置208、211、214和333处的额外突变相关。在这项研究中，我们调查了表型ZDV-R确定的重组病毒检测（抗病毒图; Virco）在223个临床样本与上述基因型的变化。223例临床样本中有150例存在M184 V突变。表型ZDV-R的范围为0.3- 5，338倍。16个样品（15个具有高ZDV-R，范围从90到3，571倍）包含MNR相关模式。对经典突变模式的分析广泛地表明，随着ZDV突变数量的增加，ZDV-R增加。当仅相对于T215 Y/F突变分析ZDV-R时，获得了相当的相关性。定点诱变实验研究了额外的突变H208 Y、R211 K和L214 F对ZDV-R的影响，当将R211 K/L214 F或H208 Y/R211 K/L214 F突变分别添加到高ZDV-R病毒中时，ZDV-R增加了7.4倍或21倍。在我们分析的临床样本数据集中，R211 K/L214 F组合出现的频率最高。H208 Y变化仅在高度ZDV-R病毒中检测到，而G333 E/D变化均匀分布。所有变化均与M184 V突变无关。在含有R211 K/L214 F或H208 Y/R211 K/L214 F突变的高ZDV-R临床样本中，分别观察到ZDV-R增加2.4倍或8倍。我们已经证明，HIV-1 RT中额外突变H208 Y、R211 K和L214 F的组合可能影响ZDV-R，在评估ZDV-R时应予以考虑。
ABSTRACT Zidovudine resistance (ZDV-R) is associated with classic genotypic changes at codons 41, 67, 70, 210, 215, and 219 of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) gene as well as with the multinucleoside resistance (MNR) complexes (Q151M MNR complex; 6-bp insertion/A62V complex). In addition, enhanced resistance to ZDV in the context of the classic ZDV mutations plus the M184V mutation has been associated with additional mutations at positions 208, 211, 214, and 333. In this study we investigated phenotypic ZDV-R determined by a recombinant virus assay (Antivirogram; Virco) in 223 clinical samples in relation to the above genotypic changes. 150 out of 223 clinical samples had the M184V mutation. Phenotypic ZDV-R ranged from 0.3- to 5,338-fold. Sixteen samples (15 with high ZDV-R ranging from 90- to 3,571-fold) contained MNR-associated patterns. Analysis of classic mutational patterns broadly demonstrated increasing ZDV-R with increasing number of ZDV mutations. A comparable correlation was obtained when ZDV-R was analyzed only relative to the T215Y/F mutation. Site-directed mutagenesis experiments investigating the influence of the additional mutations H208Y, R211K, and L214F on ZDV-R resulted in a 7.4- or 21-fold increase in ZDV-R when the R211K/L214F or H208Y/R211K/L214F mutations, respectively, were added to a highly ZDV-R virus. In the clinical sample data set we analyzed, the combination of R211K/L214F appeared most frequently. The H208Y change was detected only in highly ZDV-R viruses, whereas the G333E/D change was distributed equally. All changes were independent of the M184V mutation. A 2.4- or 8-fold increase in ZDV-R was observed in the clinical samples with high ZDV-R containing the R211K/L214F or H208Y/R211K/L214F mutations, respectively. We have shown that the combination of the additional mutations H208Y, R211K, and L214F in HIV-1 RT may influence ZDV-R and should be considered when assessing ZDV-R.
影响因子：
56.9
作者：
LARDER, BA;DARBY, G;RICHMAN, DD
通讯作者：
RICHMAN, DD