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首页> 外文期刊>Journal of Medical Virology >Mutational patterns and correlated amino acid substitutions in the HIV-1 protease after virological failure to nelfinavir- and lopinavir/ritonavir-based treatments.
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Mutational patterns and correlated amino acid substitutions in the HIV-1 protease after virological failure to nelfinavir- and lopinavir/ritonavir-based treatments.

机译：对基于奈非那韦和洛匹那韦/利托那韦的治疗在病毒学上失败后，HIV-1蛋白酶的突变模式和相关的氨基酸取代。

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摘要

Human immunodeficiency virus type 1 (HIV-1) antiviral drug resistance is a major consequence of therapy failure and compromises future therapeutic options. Nelfinavir and lopinavir/ritonavir-based therapies have been widely used in the treatment of HIV-infected patients, in combination with reverse transcriptase inhibitors. The aim of this observational study was the identification and characterization of mutations or combinations of mutations associated with resistance to nelfinavir and lopinavir/ritonavir in treated patients. Nucleotide sequences of 1,515 subtype B HIV-1 isolates from 1,313 persons with different treatment histories (including naive and treated patients) were collected in 31 Spanish hospitals over the years 2002-2005. Chi-square contingency tests were performed to detect mutations associated with failure to protease inhibitor-based therapies, and correlated mutations were identified using statistical methods. Virological failure to nelfinavir was associated with two different mutational pathways. D30N and N88D appeared mostly in patients without previous exposure to protease inhibitors, while K20T was identified as a secondary resistance mutation in those patients. On the other hand, L90M together with L10I, I54V, A71V, G73S, and V82A were selected in protease inhibitor-experienced patients. A series of correlated mutations including L10I, M46I, I54V, A71V, G73S, and L90M appeared as a common cluster of amino acid substitutions, associated with failure to lopinavir/ritonavir-based treatments. Despite the relatively high genetic barrier of some protease inhibitors, a relatively small cluster of mutations, previously selected under drug pressure, can seriously compromise the efficiency of nelfinavir- and lopinavir/ritonavir-based therapies.
机译：人类1型免疫缺陷病毒（HIV-1）抗病毒药物耐药性是治疗失败的主要结果，并损害了未来的治疗选择。基于Nelfinavir和lopinavir / ritonavir的疗法已与逆转录酶抑制剂联合用于治疗HIV感染的患者。这项观察性研究的目的是鉴定和表征与耐奈非那韦和洛匹那韦/利托那韦耐药相关的突变或突变组合。在2002年至2005年间，从31家西班牙医院中收集了来自1,313名具有不同治疗史的人（包括未治疗和治疗过的患者）的1,515株B亚型HIV-1分离株的核苷酸序列。进行卡方应变测试以检测与基于蛋白酶抑制剂的疗法失败相关的突变，并使用统计学方法鉴定相关的突变。奈非那韦的病毒学失败与两种不同的突变途径有关。 D30N和N88D大多出现在以前未接触蛋白酶抑制剂的患者中，而K20T被确定为这些患者的继发性耐药突变。另一方面，在有蛋白酶抑制剂经验的患者中选择了L90M以及L10I，I54V，A71V，G73S和V82A。一系列相关的突变，包括L10I，M46I，I54V，A71V，G73S和L90M，是氨基酸取代的常见簇，与基于lopinavir / ritonavir的治疗失败相关。尽管某些蛋白酶抑制剂的遗传屏障相对较高，但先前在药物压力下选择的相对较小的突变簇会严重损害基于奈非那韦和洛匹那韦/利托那韦的疗法的效率。

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