Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, 50931 Cologne, Germany.
Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, 50931 Cologne, Germany.
Cell. 2020 Feb 6;180(3):471-489.e22. doi: 10.1016/j.cell.2020.01.010. Epub 2020 Jan 30.
Broadly neutralizing antibodies (bNAbs) represent a promising approach to prevent and treat HIV-1 infection. However, viral escape through mutation of the HIV-1 envelope glycoprotein (Env) limits clinical applications. Here we describe 1-18, a new V1-46-encoded CD4 binding site (CD4bs) bNAb with outstanding breadth (97%) and potency (GeoMean IC = 0.048 μg/mL). Notably, 1-18 is not susceptible to typical CD4bs escape mutations and effectively overcomes HIV-1 resistance to other CD4bs bNAbs. Moreover, mutational antigenic profiling uncovered restricted pathways of HIV-1 escape. Of most promise for therapeutic use, even 1-18 alone fully suppressed viremia in HIV-1-infected humanized mice without selecting for resistant viral variants. A 2.5-Å cryo-EM structure of a 1-18-BG505 Env complex revealed that these characteristics are likely facilitated by a heavy-chain insertion and increased inter-protomer contacts. The ability of 1-18 to effectively restrict HIV-1 escape pathways provides a new option to successfully prevent and treat HIV-1 infection.
广谱中和抗体（bNAbs）代表了预防和治疗 HIV-1 感染的一种很有前途的方法。然而，HIV-1 包膜糖蛋白（Env）的突变导致病毒逃逸，限制了其临床应用。在这里，我们描述了一种新的 V1-46 编码的 CD4 结合位点（CD4bs）bNAb，称为 1-18，它具有出色的广度（97%）和效力（GeoMean IC50 = 0.048 μg/mL）。值得注意的是，1-18 不易受到典型的 CD4bs 逃逸突变的影响，并能有效克服 HIV-1 对其他 CD4bs bNAb 的耐药性。此外，抗原突变分析揭示了 HIV-1 逃逸的受限途径。最有希望用于治疗的是，即使单独使用 1-18，也能在不选择耐药病毒变异体的情况下，完全抑制感染 HIV-1 的人源化小鼠的病毒血症。1-18-BG505 Env 复合物的 2.5 Å 冷冻电镜结构表明，这些特性可能是由重链插入和增加的蛋白间接触所促进的。1-18 能够有效地限制 HIV-1 逃逸途径，为成功预防和治疗 HIV-1 感染提供了新的选择。
