CCR5 抗体 HGS004 和 HGS101 优先抑制药物结合的 CCR5 感染，并恢复原发性细胞中马拉维若耐药 HIV-1 的药物敏感性。
CCR5 antibodies HGS004 and HGS101 preferentially inhibit drug-bound CCR5 infection and restore drug sensitivity of Maraviroc-resistant HIV-1 in primary cells.
机构信息
Institute of Human Virology, University of Maryland School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
出版信息
Virology. 2011 Mar 1;411(1):32-40. doi: 10.1016/j.virol.2010.12.029. Epub 2011 Jan 12.
R5 HIV-1 strains resistant to the CCR5 antagonist Maraviroc (MVC) can use drug-bound CCR5. We demonstrate that MVC-resistant HIV-1 exhibits delayed kinetics of coreceptor engagement and fusion during drug-bound versus free CCR5 infection of cell lines. Antibodies directed against the second extracellular loop (ECL2) of CCR5 had greater antiviral activity against MVC-bound compared to MVC-free CCR5 infection. However, in PBMCs, only ECL2 CCR5 antibodies HGS004 and HGS101, but not 2D7, inhibited infection by MVC resistant HIV-1 more potently with MVC-bound than with free CCR5. In addition, HGS004 and HGS101, but not 2D7, restored the antiviral activity of MVC against resistant virus in PBMCs. In flow cytometric studies, CCR5 binding by the HGS mAbs, but not by 2D7, was increased when PBMCs were treated with MVC, suggesting MVC increases exposure of the relevant epitope. Thus, HGS004 and HGS101 have antiviral mechanisms distinct from 2D7 and could help overcome MVC resistance.
对 CCR5 拮抗剂马拉维若（MVC）耐药的 R5 HIV-1 株可以利用药物结合的 CCR5。我们证明，与游离 CCR5 感染细胞系相比，药物结合的 MVC 耐药 HIV-1 在核心受体结合和融合过程中表现出延迟的动力学。针对 CCR5 第二细胞外环（ECL2）的抗体对结合 MVC 的 CCR5 具有比游离 MVC 更强的抗病毒活性。然而，在 PBMC 中，只有 ECL2 CCR5 抗体 HGS004 和 HGS101，而不是 2D7，在结合 MVC 的情况下比游离 CCR5 更有效地抑制 MVC 耐药 HIV-1 的感染。此外，HGS004 和 HGS101，但不是 2D7，恢复了 MVC 对 PBMC 中耐药病毒的抗病毒活性。在流式细胞术研究中，当用 MVC 处理 PBMC 时，HGS mAbs 而不是 2D7 与 CCR5 的结合增加，这表明 MVC 增加了相关表位的暴露。因此，HGS004 和 HGS101 具有与 2D7 不同的抗病毒机制，可能有助于克服 MVC 耐药性。
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