Prediction of Abacavir Resistance from Genotypic Data: Impact of Zidovudine and Lamivudine Resistance In Vitro and In Vivo
Prediction of Abacavir Resistance from Genotypic Data: Impact of Zidovudine and Lamivudine Resistance In Vitro and In Vivo
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从基因型数据预测阿巴卡韦耐药性：齐多夫定和拉米夫定耐药性的体外和体内影响
DOI：
10.1128/aac.46.1.89-94.2002
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发表时间：
2002
影响因子：
4.9
通讯作者：
K. Korn
中科院分区：
文献类型：
--
作者：
H. Walter;B. Schmidt;M. Werwein;E. Schwingel;K. Korn
摘要阿巴卡韦作为一种有效的核苷逆转录酶抑制剂(NRTI)，经常用于抗逆转录病毒的联合治疗。阿巴卡韦在体内外筛选了四个突变：K65R、L74V、Y115F和M184V。在NRTI多药耐药样本中也观察到阿巴卡韦耐药。此外，阿巴卡韦耐药已在齐多夫定耐药的背景下描述。为探讨阿巴卡韦耐药的遗传基础，对307例患者样本进行了病毒基因分型和表型耐药分析。低水平和高水平的电阻分别被定义为敏感度降低2.5到5.5倍和5.5倍。如果所有具有阿巴卡韦选择和NRTI多药耐药相关突变的样本都被评为耐药，27.6%的样本被错误分类，主要是因为样本被错误地评分为敏感。因此，对其他突变的相对频率进行了评估。密码子44和118的突变在阿巴卡韦敏感样本中很少检测到，但在耐药样本中出现过多。E44D、V118I和M184V的定点突变导致双突变体44/184和三突变体44/184产生低水平抗性。还检测到仅携带齐多夫定突变的病毒克隆对阿巴卡韦的低水平耐药性。在齐多夫定背景中额外插入M184V使耐药性增加一倍，而44/118没有导致进一步增加。将齐多夫定突变和M184V的组合纳入评分系统显著减少了误分类样本的数量，而44/118并没有改善预测。综上所述，M184V与齐多夫定突变的结合导致了阿巴卡韦的高水平耐药，这可能与临床相关。因此，有效的NRTI顺序组合的选择是有限的。
ABSTRACT Abacavir is frequently used in antiretroviral combination therapies as a potent nucleoside reverse transcriptase inhibitor (NRTI). Four mutations are selected for by abacavir in vitro and in vivo: K65R, L74V, Y115F, and M184V. Abacavir resistance has also been observed in NRTI multidrug-resistant samples. Furthermore, abacavir resistance has been described in the context of zidovudine resistance. To evaluate the genetic basis of abacavir resistance, the viral genotype and phenotypic resistance were analyzed for 307 patient samples. Low- and high-level resistances were defined as 2.5- to 5.5-fold- and >5.5-fold-reduced susceptibility, respectively. If all samples with abacavir-selected and NRTI multidrug resistance-associated mutations were scored as resistant, 27.6% of the samples were misclassified, mainly due to samples falsely scored as susceptible. Therefore, the relative frequencies of other mutations were evaluated. Mutations at codons 44 and 118 were rarely detected in abacavir-susceptible samples but were overrepresented in resistant samples. Site-directed mutagenesis of E44D, V118I, and M184V resulted in low-level resistance for the double mutant 44/184 and the triple mutant. Low-level abacavir resistance was also detected for a viral clone carrying zidovudine mutations only. Additional insertion of M184V into the zidovudine background doubled the resistance, whereas 44/118 did not lead to a further increase. Incorporating combinations of zidovudine mutations and M184V into the scoring system markedly reduced the number of misclassified samples, whereas 44/118 did not improve the prediction. In conclusion, the combination of M184V with zidovudine mutations gives rise to high-level abacavir resistance, which may be clinically relevant. Thus, options for useful sequential combinations of NRTI are limited.
影响因子：
3.5
作者：
HO, SN;HUNT, HD;PEASE, LR
通讯作者：
PEASE, LR