Development of Neutralization Breadth against Diverse HIV-1 by Increasing Ab-Ag Interface on V2.
Development of Neutralization Breadth against Diverse HIV-1 by Increasing Ab-Ag Interface on V2.
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DOI：
10.1002/advs.202200063
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发表时间：
2022-05
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了解针对HIV-1的广泛中和抗体（bnAb）的成熟途径可以为HIV-1疫苗开发提供高度信息。现在从长期SHIV感染的猕猴中获得了J 038 bnAb的谱系。J 038可中和全球54%的HIV-1病毒株。其结合诱导三聚体包膜糖蛋白中的V2环之一的独特“向上”构象，并且严重依赖于聚糖，聚糖提供了近一半的结合表面。它们未变异的共同祖先能中和自体病毒。连续成熟通过扩大与种系编码残基接触的核心区域周围的抗体-Env接触面积，增强J 038谱系抗体的中和效力和宽度。本文揭示的J 038谱系抗体的发育细节和识别特征为V2靶向bnAb的诱导和成熟提供了新的途径。广泛中和抗体J 038从长期SHIV感染的猕猴中获得。J 038可中和全球54%的HIV-1病毒株。它与独特的“向上”V2顶点构象结合，与HIV-1包膜糖蛋白有效相互作用，并严重依赖聚糖。结构建模表明，它通过扩大抗体-Env接触面积在其成熟过程中增加中和宽度。
Understanding maturation pathways of broadly neutralizing antibodies (bnAbs) against HIV‐1 can be highly informative for HIV‐1 vaccine development. A lineage of J038 bnAbs is now obtained from a long‐term SHIV‐infected macaque. J038 neutralizes 54% of global circulating HIV‐1 strains. Its binding induces a unique “up” conformation for one of the V2 loops in the trimeric envelope glycoprotein and is heavily dependent on glycan, which provides nearly half of the binding surface. Their unmutated common ancestor neutralizes the autologous virus. Continuous maturation enhances neutralization potency and breadth of J038 lineage antibodies via expanding antibody‐Env contact areas surrounding the core region contacted by germline‐encoded residues. Developmental details and recognition features of J038 lineage antibodies revealed here provide a new pathway for elicitation and maturation of V2‐targeting bnAbs. A broadly neutralizing antibody, J038, is obtained from a long‐term SHIV‐infected macaque. J038 neutralizes 54% of global circulating HIV‐1 strains. It binds to a unique “up” V2 apex conformation for efficient interaction with HIV‐1 envelope glycoprotein and is heavily dependent on glycans. Structure modeling shows that it increases neutralization breadth during its maturation via expanding antibody‐Env contact areas.
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3
作者：
Piehler B;Nelson EK;Eckels J;Ramsay S;Lum K;Wood B;Greene KM;Gao H;Seaman MS;Montefiori DC;Igra M
通讯作者：
Igra M