Su C, Melby T, DeMasi R, Ravindran P, Heilek-Snyder G
Roche Pharmaceuticals, Palo Alto, CA 94304, USA.
J Clin Virol. 2006 Aug;36(4):249-57. doi: 10.1016/j.jcv.2006.03.007. Epub 2006 Jun 9.
Previous studies have established the importance of substitutions at amino acids 36-45 of HIV-1 gp41 in the development of viral resistance to the peptide fusion inhibitor enfuvirtide. However, the influence of other loci in the HIV-1 envelope is not well established.
To identify positions showing genotypic changes that are associated with particularly high levels of changes in enfuvirtide susceptibility.
We examined full-length baseline and on treatment sequences of gp120 and gp41 for isolates from 369 patients in Phase III studies of enfuvirtide, including 281 patients receiving ENF+OB and 88 patients receiving OB alone. Individual changes in gp41 and gp120 were evaluated for correlations with on treatment phenotype changes by analysis of variance (ANOVA). This modeling was done with (two-way) and without (one-way) ANOVA adjusting for the effects of any changes in gp41 amino acids 36-45 modeled as a single variable (ANY(36-45)). Positions displaying significance levels of p<0.05 by either one- or two-way ANOVA were then studied by multi-way ANOVA (stepwise regression).
In addition to changes at gp41 amino acids 36-45, changes at three positions in the HR2 domain (126, 129 and 133) occurred significantly more often in patients undergoing virologic failure on enfuvirtide. However, ANY(36-45) alone accounted for slightly more than 90% of the variation in phenotype explained by the ANOVA models. Relative to ANY(36-45) alone, significant increases in the geometric mean of the fold-change in inhibitory concentration (19.6-236.3-fold higher) were observed for amino acid changes at positions gp41: 18, 42,126, 247, 256 and 312; gp120: 330, 389 and 424 and significant reductions (18.8-29.7-fold lower) for gp41: 3, 46, 165, 232 and 324.
This study represents a statistical approach to highlight positions in HIV envelope that undergo mutations in the presence of enfuvirtide. Several of the identified positions have been implicated in the viral fusion process by other studies. The specific impact of positions 330. Three hundred and eighty-nine and 424 on viral fusion kinetics remains to be studied further by site-directed mutagenesis experiments.
先前的研究已证实，HIV-1 gp41 氨基酸 36 - 45 位点的替换在病毒对肽类融合抑制剂恩夫韦肽产生耐药性的过程中具有重要作用。然而，HIV-1 包膜中其他位点的影响尚未明确。
确定与恩夫韦肽敏感性变化水平特别高相关的基因型变化位点。
我们检查了恩夫韦肽 III 期研究中 369 例患者分离株的 gp120 和 gp41 的全长基线及治疗序列，其中包括 281 例接受恩夫韦肽 + 其他药物（OB）治疗的患者和 88 例仅接受 OB 治疗的患者。通过方差分析（ANOVA）评估 gp41 和 gp120 的个体变化与治疗表型变化的相关性。该建模在有（双向）和无（单向）ANOVA 调整的情况下进行，将 gp41 氨基酸 36 - 45 的任何变化作为单个变量（ANY(36 - 45)）进行建模。然后通过多因素方差分析（逐步回归）研究通过单向或双向 ANOVA 显示 p<0.05 显著性水平的位点。
除了 gp41 氨基酸 36 - 45 位点的变化外，HR2 结构域中三个位点（126、129 和 133）的变化在接受恩夫韦肽治疗出现病毒学失败的患者中显著更频繁发生。然而，ANY(36 - 45) 单独解释的表型变异略超过 ANOVA 模型解释变异的 90%。相对于单独的 ANY(36 - 45)，观察到 gp41 位点 18、42、126、247、256 和 312；gp120 位点 330、389 和 424 的氨基酸变化导致抑制浓度变化倍数的几何平均值显著增加（高 19.6 - 236.3 倍），而 gp41 位点 3、46、165、232 和 324 的变化导致显著降低（低 18.8 - 29.7 倍）。
本研究采用统计方法突出了在恩夫韦肽存在下 HIV 包膜中发生突变的位点。其他研究已表明其中一些已确定的位点与病毒融合过程有关。330、389 和 424 位点对病毒融合动力学的具体影响仍有待通过定点诱变实验进一步研究。
