Mapping resistance to the CCR5 co-receptor antagonist vicriviroc using heterologous chimeric HIV-1 envelope genes reveals key determinants in the C2-V5 domain of gp120
Mapping resistance to the CCR5 co-receptor antagonist vicriviroc using heterologous chimeric HIV-1 envelope genes reveals key determinants in the C2-V5 domain of gp120
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DOI：
10.1016/j.virol.2007.12.009
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发表时间：
2008-04-10
期刊：
影响因子：
3.7
通讯作者：
Howe, John A.
中科院分区：
文献类型：
--
作者：
Ogert, Robert A.;Wojcik, Lisa;Howe, John A.
几种与宿主CCR5共受体结合并防止病毒进入的小分子药物已被开发出来用于治疗HIV-1感染。在HIV-1包膜中发现的先天变异性和进入过程中复杂的病毒/细胞相互作用使得对这些抑制剂的耐药性的定义具有挑战性。在这里，我们发现从原代分离物RU570-VCV(RES)中定位gp160基因的决定因素变得复杂，因为克隆的包膜基因在伪病毒检测中处于失活状态。因此，我们将RU570-VCV(RES)的包膜重组为高度活性和易感的ADA gp160骨架。嵌合包膜在伪病毒检测中产生了强大的信号，在单循环检测和复制病毒时，需要一个200个氨基酸的片段，包括RU570-VCV(RES)包膜的C2-V5区域，以提供抗性。相反，只包含这种耐药病毒V3-环区的嵌合包膜是完全敏感的，这表明获得的V3-环变化是上下文相关的。(C)2007 Elsevier Inc.保留所有权利。
Several small molecule drugs that bind to the host CCR5 co-receptor and prevent viral entry have been developed for the treatment of HIV-1 infection. The innate variability found in HIV-1 envelope and the complex viral/cellular interactions during entry makes defining resistance to these inhibitors challenging. Here we found that mapping determinants in the gp160 gene from a primary isolate RU570-VCV(res), selected in culture for resistance to the CCR5 entry inhibitor vicriviroc, was complicated by inactivity of the cloned envelope gene in pseudovirus assays. We therefore recombined the envelope from RU570-VCV(res), into a highly active and susceptible ADA gp160 backbone. The chimeric envelopes generated robust signals in the pseudovirus assay and a 200 amino acid fragment, encompassing a C2-V5 region of the RU570-VCV(res) envelope, was required to confer resistance in both the single-cycle assay and in replicating virus. In contrast, a chimeric envelope that contained only the V3-loop region from this resistant virus was completely susceptible suggesting that the V3-loop changes acquired are context dependent. (C) 2007 Elsevier Inc. All rights reserved.