Activity of the HIV-1 Attachment Inhibitor BMS-626529, the Active Component of the Prodrug BMS-663068, against CD4-Independent Viruses and HIV-1 Envelopes Resistant to Other Entry Inhibitors
Activity of the HIV-1 Attachment Inhibitor BMS-626529, the Active Component of the Prodrug BMS-663068, against CD4-Independent Viruses and HIV-1 Envelopes Resistant to Other Entry Inhibitors
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DOI：
10.1128/aac.00513-13
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发表时间：
2013-09-01
影响因子：
4.9
通讯作者：
Krystal, Mark
中科院分区：
文献类型：
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作者：
Li, Zhufang;Zhou, Nannan;Krystal, Mark
BMS-626529是一种新型的小分子HIV-1附着抑制剂，对CCR5和CXCR4嗜性病毒都有活性。Bms-626529通过阻止gp120与cd4结合而发挥作用。这种化合物的前药BMS-663068目前正在临床开发中。由于BMS-663068的理论抗性途径可能是CD_4非依赖表型的发展，我们检测了BMS-626529对CD_4非依赖病毒的活性，并研究了BMS-626529的抗性是否与CD_4非依赖的表型有关。最后，我们评估了BMS-626529与其他HIV-1进入抑制剂之间是否存在交叉耐药性。检测了两个具有CD4非依赖表型的实验室来源的包膜(一个是CXCR4嗜性的，一个是CCR5嗜性的)，五个来自临床分离株的包膜，以及几个位点特异性突变的包膜，以了解它们对包膜病毒的感染性或对626529的敏感性。对其他进入抑制剂(恩福韦肽、马拉韦罗和伊巴利单抗)具有耐药性的病毒也被检测了对BMS-626529的敏感性。这两个不依赖于c4的实验室分离株在c4(-)细胞中保持对bms-626529的敏感性，而来自对bms-626529具有抗药性的病毒的HIV-1包膜没有表现出cd4不依赖的表型的证据。BMS-626529还显示出对伊巴利单抗和恩福韦林抗性包膜的抑制活性。虽然马拉韦罗抗性与对bms-626529敏感性降低之间似乎存在某种关联，但不能假定存在绝对的相关性，因为一些CCR5嗜马拉韦罗的包膜对bms-626529仍然敏感。临床使用前药BMS-663068不太可能通过产生非依赖于CD_4的病毒来促进耐药性。在BMS-626529和其他艾滋病毒进入抑制剂之间没有观察到交叉耐药性，这可以允许与不同类别的进入抑制剂顺序或同时使用。
BMS-626529 is a novel small-molecule HIV-1 attachment inhibitor active against both CCR5- and CXCR4-tropic viruses. BMS-626529 functions by preventing gp120 from binding to CD4. A prodrug of this compound, BMS-663068, is currently in clinical development. As a theoretical resistance pathway to BMS-663068 could be the development of a CD4-independent phenotype, we examined the activity of BMS-626529 against CD4-independent viruses and investigated whether resistance to BMS-626529 could be associated with a CD4-independent phenotype. Finally, we evaluated whether cross-resistance exists between BMS-626529 and other HIV-1 entry inhibitors. Two laboratory-derived envelopes with a CD4-independent phenotype (one CXCR4 tropic and one CCR5 tropic), five envelopes from clinical isolates with preexisting BMS-626529 resistance, and several site-specific mutant BMS-626529-resistant envelopes were examined for their dependence on CD4 for infectivity or susceptibility to BMS-626529. Viruses resistant to other entry inhibitors (enfuvirtide, maraviroc, and ibalizumab) were also examined for susceptibility to BMS-626529. Both CD4-independent laboratory isolates retained sensitivity to BMS-626529 in CD4(-) cells, while HIV-1 envelopes from viruses resistant to BMS-626529 exhibited no evidence of a CD4-independent phenotype. BMS-626529 also exhibited inhibitory activity against ibalizumab- and enfuvirtide-resistant envelopes. While there appeared to be some association between maraviroc resistance and reduced susceptibility to BMS-626529, an absolute correlation cannot be presumed, since some CCR5-tropic maraviroc-resistant envelopes remained sensitive to BMS-626529. Clinical use of the prodrug BMS-663068 is unlikely to promote resistance via generation of CD4-independent virus. No cross-resistance between BMS-626529 and other HIV entry inhibitors was observed, which could allow for sequential or concurrent use with different classes of entry inhibitors.