通过高度广泛和强大的中和抗体限制HIV-1逃逸
Philipp Schommers1, Henning Gruell2, Morgan E Abernathy3
1Laboratory 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.
Cell
|February 1, 2020
概括
一种新的广泛中和抗体 (bNAb) 1-18 显示出对HIV-1 的高强度和广度. 这种抗体有效地克服了小鼠的病毒逃逸和完全抑制的病毒病,提供了一个有前途的新HIV-1预防和治疗策略.
科学领域:
- 免疫学
- 病毒学
- 结构生物学
背景情况:
- 广泛中和抗体 (bNAbs) 对于预防和治疗HIV-1至关重要.
- 艾滋病毒-1包膜糖蛋白 (Env) 突变导致病毒逃逸,限制了bNAb的疗效.
- CD4结合部位 (CD4bs) bNAbs是主要的目标,但耐药性仍然是一个挑战.
研究的目的:
- 描述一种新的CD4bsbNAb,1-18,其宽度,功效和对HIV-1逃逸的抵抗力.
- 研究1-18对抗抗性HIV-1变体的有效性背后的机制.
- 在临床前模型中评估1-18的治疗潜力.
主要方法:
- 对bNAb 1-18的结合范围和强度 (IC50) 对各种HIV-1分离物的表征.
- 对常见的CD4bs脱离突变的1-18活动的评估.
- 突变抗原分析以确定HIV-1逃生途径.
- 在HIV-1感染的人类化小鼠体内疗效研究.
- 用冷电子显微镜 (cryo-EM) 确定1-18-Env复合物的结构.
主要成果:
- 1-18 具有97%的宽度和高强度 (地质平均IC50=0. 048μg/ ml) 对抗HIV-1.
- 对典型的CD4bs脱离突变有效,并克服对其他CD4bsbNAbs的抵抗.
- 突变分析显示HIV-1的逃生途径受到限制.
- 在没有选择耐药变种的人性化小鼠中,单独使用1-18完全抑制了病毒性.
- 化EM结构显示重链插入和增加的原体间接触有助于1-18的特性.
结论:
- 这种抗体具有对HIV-1的独特抗药性.
- 抗体的结构特征可能有助于限制病毒逃逸的能力.
- 由于其有效性和克服耐药性的能力,该药物是HIV-1预防和治疗的有希望的治疗候选药物.
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