An anti-CCR5 monoclonal antibody and small molecule CCR5 antagonists synergize by inhibiting different stages of human immunodeficiency virus type 1 entry.
An anti-CCR5 monoclonal antibody and small molecule CCR5 antagonists synergize by inhibiting different stages of human immunodeficiency virus type 1 entry.
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DOI：
10.1016/j.virol.2006.05.016
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发表时间：
2006-09
期刊：
影响因子：
3.7
通讯作者：
Diana Safarian;Xavier Carnec;Fotini Tsamis;F. Kajumo;T. Dragic
中科院分区：
文献类型：
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作者：
Diana Safarian;Xavier Carnec;Fotini Tsamis;F. Kajumo;T. Dragic
HIV-1共受体是新型抗病毒药物的有吸引力的靶点。这里，研究了两类CCR 5拮抗剂对进入的抑制。我们证实了先前的发现，即HIV-1分离株对CCR 5介导的进入的小分子抑制剂SCH-C和TAK-779的敏感性差异很大。相反，抗CCR 5单克隆抗体（PA 14）类似地抑制不同病毒分离株的进入。对小分子的敏感性是V3环依赖性的，并且与gp 120与CCR 5结合的水平成反比。此外，单克隆抗体和小分子的组合在阻断HIV-1进入方面具有高度协同作用，表明不同的作用机制。这通过抑制实验的时间过程证实，其中PA 14 MAb和小分子显示抑制CCR 5使用的时间上不同的阶段。我们提出，小分子抑制V3结合到第二个细胞外环的CCR 5，而PA 14优先抑制后续事件，如CCR 5招募到融合复合物或构象变化的gp 120-CCR 5复合物，触发融合。重要的是，我们的研究结果表明，CCR 5抑制剂与不同作用机制的组合将是控制HIV-1感染和减缓耐药菌株出现的关键。
HIV-1 coreceptors are attractive targets for novel antivirals. Here, inhibition of entry by two classes of CCR5 antagonists was investigated. We confirmed previous findings that HIV-1 isolates vary greatly in their sensitivity to small molecule inhibitors of CCR5-mediated entry, SCH-C and TAK-779. In contrast, an anti-CCR5 monoclonal antibody (PA14) similarly inhibited entry of diverse viral isolates. Sensitivity to small molecules was V3 loop-dependent and inversely proportional to the level of gp120 binding to CCR5. Moreover, combinations of the MAb and small molecules were highly synergistic in blocking HIV-1 entry, suggesting different mechanisms of action. This was confirmed by time course of inhibition experiments wherein the PA14 MAb and small molecules were shown to inhibit temporally distinct stages of CCR5 usage. We propose that small molecules inhibit V3 binding to the second extracellular loop of CCR5, whereas PA14 preferentially inhibits subsequent events such as CCR5 recruitment into the fusion complex or conformational changes in the gp120-CCR5 complex that trigger fusion. Importantly, our findings suggest that combinations of CCR5 inhibitors with different mechanisms of action will be central to controlling HIV-1 infection and slowing the emergence of resistant strains.