Malet Isabelle, Delelis Olivier, Soulie Cathia, Wirden Marc, Tchertanov Luba, Mottaz Philippe, Peytavin Gilles, Katlama Christine, Mouscadet Jean-François, Calvez Vincent, Marcelin Anne-Genevieve
UPMC Univ Paris 06, F-75005 Paris, France.
J Antimicrob Chemother. 2009 Apr;63(4):795-804. doi: 10.1093/jac/dkp014. Epub 2009 Feb 16.
Raltegravir is the first approved inhibitor of HIV-1 integrase (IN). In most patients, raltegravir failure is associated with mutations in the IN gene, through two different genetic pathways: 155 (N155H) or 148 (Q148K/R/H). The objective of this study was to characterize the dynamics of HIV-1 quasispecies variant populations in patients who failed to respond to raltegravir treatment.
Bulk genotyping and clonal analysis were performed during the follow-up of 10 patients who failed to respond to raltegravir treatment.
Treatment failed through the 155 pathway in six patients and through the 148 pathway in two patients; two further patients switched from the 155 to the 148 pathway. In the two patients switching from the 155 to the 148 pathway, clonal analysis showed that Q148R/H and N155H mutations were present on different strands, suggesting that these two pathways are independent. This was consistent with our finding that each genetic profile was associated with different secondary mutations. We observed a greater variability among quasispecies associated with the 155 pathway, and IC(50) determinations showed that the fold resistance to raltegravir, relative to wild-type, was 10 for the N155H mutant and 50 for the G140S+Q148H mutant.
Clonal analysis strongly suggests that the two main genetic pathways, 155 and 148, involved in the development of resistance to raltegravir are independent and exclusive. Moreover, the switch of the resistance profile from 155 to 148 may be related to the higher level of resistance to raltegravir conferred by the 148 pathway and also to the higher instability of the 155 pathway.
雷特格韦是首个获批的HIV-1整合酶（IN）抑制剂。在大多数患者中，雷特格韦治疗失败与IN基因的突变有关，通过两种不同的遗传途径：155（N155H）或148（Q148K/R/H）。本研究的目的是描述对雷特格韦治疗无反应的患者中HIV-1准种变异群体的动态变化。
对10例对雷特格韦治疗无反应的患者进行随访期间，进行了群体基因分型和克隆分析。
6例患者通过155途径治疗失败，2例患者通过148途径治疗失败；另外2例患者从155途径转换为148途径。在从155途径转换为148途径的2例患者中，克隆分析显示Q148R/H和N155H突变存在于不同链上，表明这两种途径是独立的。这与我们的发现一致，即每种基因谱都与不同的继发突变相关。我们观察到与155途径相关的准种之间变异性更大，IC50测定表明，相对于野生型，N155H突变体对雷特格韦的耐药倍数为10，G140S+Q148H突变体为50。
克隆分析有力地表明，参与雷特格韦耐药性产生的两条主要遗传途径155和148是独立且互斥的。此外，耐药谱从155转换为148可能与148途径赋予的对雷特格韦更高水平的耐药性以及155途径更高的不稳定性有关。
