Laboratory of Retrovirology, CRP-Santé, Luxembourg, Luxembourg.
PLoS One. 2011;6(7):e21535. doi: 10.1371/journal.pone.0021535. Epub 2011 Jul 8.
Resistance mutations to the HIV-1 fusion inhibitor enfuvirtide emerge mainly within the drug's target region, HR1, and compensatory mutations have been described within HR2. The surrounding envelope (env) genetic context might also contribute to resistance, although to what extent and through which determinants remains elusive. To quantify the direct role of the env context in resistance to enfuvirtide and in viral infectivity, we compared enfuvirtide susceptibility and infectivity of recombinant viral pairs harboring the HR1-HR2 region or the full Env ectodomain of longitudinal env clones from 5 heavily treated patients failing enfuvirtide therapy. Prior to enfuvirtide treatment onset, no env carried known resistance mutations and full Env viruses were on average less susceptible than HR1-HR2 recombinants. All escape clones carried at least one of G36D, V38A, N42D and/or N43D/S in HR1, and accordingly, resistance increased 11- to 2800-fold relative to baseline. Resistance of full Env recombinant viruses was similar to resistance of their HR1-HR2 counterpart, indicating that HR1 and HR2 are the main contributors to resistance. Strictly X4 viruses were more resistant than strictly R5 viruses, while dual-tropic Envs featured similar resistance levels irrespective of the coreceptor expressed by the cell line used. Full Env recombinants from all patients gained infectivity under prolonged drug pressure; for HR1-HR2 viruses, infectivity remained steady for 3/5 patients, while for 2/5 patients, gains in infectivity paralleled those of the corresponding full Env recombinants, indicating that the env genetic context accounts mainly for infectivity adjustments. Phylogenetic analyses revealed that quasispecies selection is a step-wise process where selection of enfuvirtide resistance is a dominant factor early during therapy, while increased infectivity is the prominent driver under prolonged therapy.
HIV-1 融合抑制剂恩夫韦肽的耐药突变主要出现在药物靶点 HR1 内，并且已经在 HR2 内描述了补偿性突变。周围的包膜 (env) 遗传背景也可能有助于耐药，但程度和通过哪些决定因素仍然难以捉摸。为了量化 env 背景对恩夫韦肽耐药和病毒感染力的直接作用，我们比较了来自 5 名接受恩夫韦肽治疗失败的重度治疗患者的纵向 env 克隆的 HR1-HR2 区或全长 Env 外域重组病毒对恩夫韦肽的敏感性和感染力。在开始恩夫韦肽治疗之前，没有 env 携带已知的耐药突变，全长 Env 病毒的平均敏感性低于 HR1-HR2 重组体。所有逃逸克隆在 HR1 中都至少携带 G36D、V38A、N42D 和/或 N43D/S 之一，因此，与基线相比，耐药性增加了 11-2800 倍。全长 Env 重组病毒的耐药性与 HR1-HR2 对应物的耐药性相似，表明 HR1 和 HR2 是耐药的主要贡献者。严格的 X4 病毒比严格的 R5 病毒更耐药，而双嗜性 Env 无论细胞系表达的核心受体如何，其耐药水平相似。所有患者的全长 Env 重组体在长期药物压力下均获得了感染力；对于 HR1-HR2 病毒，对于 3/5 名患者，感染力保持稳定，而对于 2/5 名患者，感染力的增加与相应的全长 Env 重组体的增加平行，表明 env 遗传背景主要负责感染性调整。系统发育分析显示，准种选择是一个逐步的过程，在治疗早期，恩夫韦肽耐药的选择是一个主要因素，而在长期治疗下，感染性的增加是一个突出的驱动因素。
