Resistance to CCR5 inhibitors caused by sequence changes in the fusion peptide of HIV-1 gp41
Resistance to CCR5 inhibitors caused by sequence changes in the fusion peptide of HIV-1 gp41
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DOI：
10.1073/pnas.0811713106
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发表时间：
2009-03-31
影响因子：
11.1
通讯作者：
Moore, John P.
中科院分区：
文献类型：
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作者：
Anastassopoulou, Cleo G.;Ketas, Thomas J.;Moore, John P.
我们研究了HIV-1 R5主要分离株D1/85.16对小分子CCR5抑制剂维昔洛克(VVC)的耐药机制。与其他对这类化合物具有耐药性的病毒不同，D1/85.16在gp120表面糖蛋白的V3区域缺乏序列变化。与来自亲本的抑制剂敏感病毒CC1/85的env序列比较，发现gp41跨膜糖蛋白的融合多肽(FP)与耐药表型有3个保守的变化。对工程Env嵌合和点替换病毒的研究证实，这3个FP残基是VVC耐药性的主要原因，而不改变辅助受体的使用，正如在外周血单核细胞和TZM-bi细胞系中所评估的那样。VVC耐药性在两种细胞类型中表现不同，工程耐药病毒的剂量-反应曲线具有依赖于检测的复杂性。为了解释它们，我们创建了一个耐药性模型，并生成了理论上的VVC抑制曲线，该曲线与耐药病毒的实验数据非常接近。该模型的基础是存在不同形式的CCR5，对小分子CCR5抑制剂具有不同的亲和力，这些小分子CCR5抑制剂被认为在不同细胞类型上以不同的比例存在，并在与抑制剂连接时被耐药的HIV-1变种选择性地使用。综上所述，实验结果和理论模型可能有助于理解HIV-1在各种条件下如何利用CCR5进入靶细胞。
We have investigated the mechanism of resistance of a HIV type 1 (HIV-1) R5 primary isolate, D1/85.16, to the small molecule CCR5 inhibitor, vicriviroc (VVC). Unlike other viruses resistant to this class of compound, D1/85.16 lacks sequence changes in the V3 region of the gp120 surface glycoprotein. Inspection of env sequences from D1/85.16 compared with those derived from the parental, inhibitor-sensitive virus, CC1/85, revealed a cluster of 3 conservative changes in the fusion peptide (FP) of the gp41 transmembrane glycoprotein that tracked with the resistance phenotype. Studies with engineered Env-chimeric and point-substituted viruses confirmed that these 3 FP residues were substantially responsible for VVC resistance without altering coreceptor usage, as assessed in both peripheral blood mononuclear cells and the TZM-bI cell line. VVC resistance is manifested differently in the 2 cell types, and there are assay-dependent complexities to the dose-response curves for the engineered resistant viruses. To explain them, we created a model for resistance and generated theoretical VVC inhibition curves that closely mimic the experimental data for the resistant viruses. The basis for the model is the existence of distinct forms of CCR5, with varying affinities for small molecule CCR5 inhibitors that are presumed to be present in different proportions on different cell types, and are used selectively by resistant HIV-1 variants when ligated with an inhibitor. Together, the experimental results and theoretical model may help understand how HIV-1 uses CCR5 to enter target cells under various conditions.