Department of Immunopathology, Post Graduate Institute of Medical Education & Research, Chandigarh 160012, India.
Antiviral Res. 2011 Nov;92(2):213-8. doi: 10.1016/j.antiviral.2011.08.005. Epub 2011 Aug 22.
Genotyping reveal emergence of drug resistance (DR)-related mutations in HIV-1 protease (PR) gene in the first-line treatment failure patients as per Stanford DR database. In order to have a subtype C specific prediction model, a three dimensional structure of local wild type C variant is created and the identified mutations were introduced to assess the mutational effects on protease inhibitors (PI) in a homology model. We estimated viral load, CD4 count and conducted DR genotyping in HIV isolates from 129 therapy naive and 20 first-line treatment failure individuals. Several genotypic variations, as compared to subtype B sequence in the Stanford gene database were detected in HIV-1 subtype C isolates from treatment naive individuals. Among these, nine mutations (12S, 15V, 19I, 36I, 41K, 63P, 69K, 89M, 93L) occurred in more than 60% of the isolates and were considered as local wild type for molecular modelling studies. No major mutations were seen in the PR sequences in isolates from treatment-naive individuals, although isolates from two patients had T74S mutation, known to be associated with reduced susceptibility to nelfinavir (NFV) and a combination of M36I, H69K and L89M mutations found in isolates from 77 patients (59.7%), considered to be conferring resistance to tipranavir (TPV) according to ANRS algorithm. Among the first-line treatment failures, an isolate from one patient showed L33F, I47T, M46G, and G48E mutations conferring intermediate resistance to saquinavir (SQV) and lopinavir (LPV). Though the docking energy scores are in agreement with this interpretation for SQV, it, however, indicated these mutations to be causing intermediate to high level resistance to atazanavir (ATV) and tipranavir (TPV) but making it susceptible to LPV. The patient finally responded to a second-line regimen containing 3TC, AZT and LPV with significant viral suppression. All the DR genotyping studies analyse the results using available databases which are all based on subtype B specific sequences. The proposed homology model in this study is unique, as it may predict subtype C specific susceptibility criteria for the available PIs.
基因分型结果显示，根据斯坦福耐药数据库，一线治疗失败患者的 HIV-1 蛋白酶（PR）基因中出现耐药相关突变。为了建立一个针对 C 亚型的特异性预测模型，我们构建了一个局部野生型 C 变异的三维结构，并引入鉴定出的突变来评估突变对蛋白酶抑制剂（PI）的影响在同源模型中。我们对 129 名未经治疗的和 20 名一线治疗失败的个体的 HIV 分离物进行了病毒载量、CD4 计数和耐药基因分型。与斯坦福基因数据库中的 B 亚型序列相比，在未经治疗的个体的 HIV-1 C 亚型分离物中检测到了几种基因型变异。其中，12S、15V、19I、36I、41K、63P、69K、89M 和 93L 这 9 个突变发生在超过 60%的分离物中，被认为是分子建模研究的本地野生型。在未经治疗的个体的 PR 序列中未发现主要突变，尽管来自两名患者的分离物具有 T74S 突变，已知该突变与奈非那韦（NFV）的敏感性降低有关，而来自 77 名患者（59.7%）的分离物中发现的 M36I、H69K 和 L89M 突变被认为对替拉那韦（TPV）有耐药性根据 ANRS 算法。在一线治疗失败的患者中，来自一名患者的分离物显示出 L33F、I47T、M46G 和 G48E 突变，对沙奎那韦（SQV）和洛匹那韦（LPV）具有中度耐药性。尽管对接能量评分与 SQV 的这一解释一致，但它表明这些突变导致对阿扎那韦（ATV）和替拉那韦（TPV）的中高水平耐药性，但使 LPV 具有敏感性。该患者最终对包含 3TC、AZT 和 LPV 的二线方案有反应，病毒载量显著降低。所有耐药基因分型研究都使用基于 B 亚型特异性序列的现有数据库分析结果。本研究中提出的同源模型是独特的，因为它可能预测针对现有 PI 的 C 亚型特异性敏感性标准。
