Si-Mohamed Ali, Piketty Christophe, Tisserand Pascaline, LeGoff Jérôme, Weiss Laurence, Charpentier Charlotte, Kazatchkine Michel D, Bélec Laurent
Laboratoire de Virologie, Hôpital Européen Georges Pompidou, Paris, France.
J Acquir Immune Defic Syndr. 2007 Jan 1;44(1):1-5. doi: 10.1097/01.qai.0000243118.59906.f4.
Sequence variations in HR-1 gp41 env gene region encoding the target for T-20 have previously been reported among patients naive to inhibitory fusion.
To evaluate whether a previous therapeutic history of patients could have an impact on a differential evolution of the gp41 polymorphism.
We assessed the genetic polymorphism within the critical HR-1 gp41 env gene region in HIV-1 variants from 108 T-20-naive patients (Groups I-III) and 12 patients receiving T-20 as part of a salvage regimen (Group IV). T-20-naive patients included 50 patients exhibiting variants harboring resistance mutations to NRTIs, NNRTIs, and PIs (Group I), 24 patients with variants harboring resistance mutations for NRTIs and/or NNRTIs (Group II), and 34 antiretroviral drug-naive patients (Group III).
In T-20-naive patients whose HIV harbored resistance mutations to NRTIs, NNRTIs, and/or PIs, the mean number of synonymous mutations (ds) per patient was decreased and the mean number of nonsynonymous (da) mutations per patient was increased, resulting in a significant decrease in the mean Sigmads/Sigmada ratio as compared with antiretroviral drug-naive patients (Group III; 4.1 vs. 11.6; P < 0.0001). The mean number of polymorphic mutations in HR-1 gp41 per patient was two-fold higher in patients exhibiting antiretroviral drug resistance mutations (Groups I and II) than in antiretroviral drug-naive patients (Group III; 0.41 vs. 0.20; P < 0.05).
Our observations indicate that the HR-1 gp41 T-20 target is subjected to high genetic variability, including intrinsic polymorphism and selection of T-20 resistance mutations under T-20 intake, that is increased by the presence of resistance mutations to NRTIs, NNRTIs, and/or PIs. Our data provide a basis for a potential impact of previous antiretroviral drug history on the therapeutic efficacy of T-20.
之前有报道称，在未接受过融合抑制剂治疗的患者中，编码T-20靶点的HR-1 gp41 env基因区域存在序列变异。
评估患者既往治疗史是否会对gp41多态性的差异进化产生影响。
我们评估了108例未接受过T-20治疗的患者（I - III组）以及12例接受T-20作为挽救治疗方案一部分的患者（IV组）的HIV-1变体中关键的HR-1 gp41 env基因区域内的基因多态性。未接受过T-20治疗的患者包括50例表现出对核苷类反转录酶抑制剂（NRTIs）、非核苷类反转录酶抑制剂（NNRTIs）和蛋白酶抑制剂（PIs）耐药突变的变体患者（I组），24例表现出对NRTIs和/或NNRTIs耐药突变的变体患者（II组），以及34例未接受过抗逆转录病毒药物治疗的患者（III组）。
在HIV对NRTIs、NNRTIs和/或PIs存在耐药突变的未接受过T-20治疗的患者中，每位患者的同义突变平均数量（ds）减少，每位患者的非同义突变平均数量（da）增加，与未接受过抗逆转录病毒药物治疗的患者（III组）相比，平均Sigmads/Sigmada比值显著降低（4.1对11.6；P < 0.0001）。表现出抗逆转录病毒药物耐药突变的患者（I组和II组）中，每位患者HR-1 gp41的多态性突变平均数量是未接受过抗逆转录病毒药物治疗的患者（III组）的两倍（0.41对0.20；P < 0.05）。
我们的观察结果表明，HR-1 gp41 T-20靶点存在高度的基因变异性，包括内在多态性以及在接受T-20治疗期间T-20耐药突变的选择，而NRTIs、NNRTIs和/或PIs的耐药突变会增加这种变异性。我们的数据为既往抗逆转录病毒药物治疗史对T-20治疗效果的潜在影响提供了依据。
