Structural development of the HIV-1 apex-directed PGT145-PGDM1400 antibody lineage.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-01-28 Epub Date: 2025-01-17 DOI:10.1016/j.celrep.2024.115223

Rosemarie D Mason, Baoshan Zhang, Nicholas C Morano, Chen-Hsiang Shen, Krisha McKee, Ashley Heimann, Renguang Du, Alexandra F Nazzari, Shelby Hodges, Tapan Kanai, Bob C Lin, Mark K Louder, Nicole A Doria-Rose, Tongqing Zhou, Lawrence Shapiro, Mario Roederer, Peter D Kwong, Jason Gorman

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引用次数: 0

Abstract

Broadly neutralizing antibodies (bNAbs) targeting the apex of the HIV-1-envelope (Env) trimer comprise the most potent category of HIV-1 bNAbs and have emerged as promising therapeutics. Here, we investigate the development of the HIV-1 apex-directed PGT145-PGDM1400 antibody lineage and report cryo-EM structures at 3.4 Å resolution of PGDM1400 and of an improved PGT145 variant (PGT145-R100aS), each bound to the BG505 Env trimer. Cross-species-based engineering improves PGT145 IC₈₀ breadth to near that of PGDM1400. Despite similar breadth and potency, the two antibodies differ in their residue-level interactions with important apex features, including N160 glycans and apex cavity, with residue 100i of PGT145 (sulfated tyrosine) penetrating ∼7 Å farther than residue 100i of PGDM1400 (aspartic acid). While apex-directed bNAbs from other donors use maturation pathways that often converge on analogous residue-level recognition, our results demonstrate that divergent residue-level recognition can occur within the same lineage, thereby enabling improved coverage of escape variants.

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HIV-1顶点导向的PGT145-PGDM1400抗体谱系的结构发展

靶向HIV-1包膜（Env）三聚体顶点的广泛中和抗体（bNAbs）是HIV-1包膜三聚体中最有效的一类抗体，已成为一种有前景的治疗方法。在这里，我们研究了HIV-1顶点导向的PGT145-PGDM1400抗体谱系的发展，并报告了3.4 Å分辨率下PGDM1400和改进的PGT145变体（PGT145- r100as）的冷冻电镜结构，它们分别与BG505 Env三聚体结合。跨物种工程将PGT145 IC80的宽度提高到接近PGDM1400。尽管宽度和效力相似，但两种抗体在残基水平上与重要的尖端特征（包括N160聚糖和尖端腔）的相互作用存在差异，其中PGT145（硫酸酪氨酸）残基100i比PGDM1400（天冬氨酸）残基100i穿透~ 7 Å远。虽然来自其他供体的apex-directed bnab使用的成熟途径通常收敛于类似的残基水平识别，但我们的研究结果表明，不同的残基水平识别可以发生在同一谱系中，从而提高了逃逸变体的覆盖率。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.