Jekle Andreas, Chow Eugene, Kopetzki Erhard, Ji Changhua, Yan Mei Jun, Nguyen Rosa, Sankuratri Surya, Cammack Nick, Heilek Gabrielle
Virology Disease Area, Roche Palo Alto LLC, Palo Alto, CA, United States.
Antiviral Res. 2009 Sep;83(3):257-66. doi: 10.1016/j.antiviral.2009.06.005. Epub 2009 Jun 25.
Resistance to antiretroviral drugs is a common problem in the treatment of HIV-1-infected patients. To overcome resistance, we generated a novel, bifunctional HIV-1 entry inhibitor by combining the anti-CD4 monoclonal antibody (mAb) 6314 with a fusion inhibitor similar to T-651 (anti-CD4 mAb based BiFunctional Fusion Inhibitor, CD4-BFFI). CD4-BFFI has potent antiviral activity against a multitude of HIV-1 isolates independent of their co-receptor usage and genetic background. It has higher antiviral potency compared to the fusion inhibitor T-651 or the anti-CD4 mAb 6314 used independently. More importantly, every HIV-1 strain tested was fully inhibited by CD4-BFFI while many strains were only partially inhibited by 6314. CD4-BFFI also retained antiviral potency against virus strains resistant to two fusion inhibitors, a CCR5 antagonist and an anti-CCR5 mAb. Pre-incubation of cells with a saturating concentration of anti-CD4 mAbs reduced the antiviral potency of CD4-BFFI, suggesting that binding of CD4-BFFI to the cell surface via its CD4 mAb portion is required for the antiviral potency of its fusion inhibitor moiety. Collectively, we present a novel HIV-1 inhibitor with a dual mode of action and excellent antiviral potency against wildtype and entry-inhibitor resistant virus strains suggesting that CD4-BFFI may have a high barrier to resistance.
对抗逆转录病毒药物产生耐药性是治疗HIV-1感染患者时的一个常见问题。为了克服耐药性，我们通过将抗CD4单克隆抗体（mAb）6314与一种类似于T-651的融合抑制剂相结合，生成了一种新型双功能HIV-1进入抑制剂（基于抗CD4 mAb的双功能融合抑制剂，CD4-BFFI）。CD4-BFFI对多种HIV-1分离株具有强大的抗病毒活性，与它们的共受体使用情况和基因背景无关。与单独使用的融合抑制剂T-651或抗CD4 mAb 6314相比，它具有更高的抗病毒效力。更重要的是，所测试的每一种HIV-1毒株都被CD4-BFFI完全抑制，而许多毒株仅被6314部分抑制。CD4-BFFI对两种融合抑制剂、一种CCR5拮抗剂和一种抗CCR5 mAb耐药的病毒株也保留了抗病毒效力。用饱和浓度的抗CD4 mAb对细胞进行预孵育会降低CD4-BFFI的抗病毒效力，这表明CD4-BFFI通过其CD4 mAb部分与细胞表面的结合对于其融合抑制剂部分的抗病毒效力是必需的。总体而言，我们展示了一种具有双重作用模式且对野生型和对进入抑制剂耐药的病毒株具有优异抗病毒效力的新型HIV-1抑制剂，这表明CD4-BFFI可能具有较高的耐药屏障。
