Transient glycan shield reduction induces CD4-binding site broadly neutralizing antibodies in SHIV-infected macaques.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-06-13 DOI:10.1016/j.celrep.2025.115848

Daniel J Morris, Jason Gorman, Tongqing Zhou, Jinery Lora, Andrew J Connell, Hui Li, Weimin Liu, Ryan S Roark, Mary S Campion, John W Carey, Rumi Habib, Yingying Li, Christian L Martella, Younghoon Park, Ajay Singh, Kirsten J Sowers, I-Ting Teng, Shuyi Wang, Neha Chohan, Wenge Ding, Craig Lauer, Emily Lewis, Rosemarie D Mason, Juliette M Rando, Lowrey Peyton, Chaim A Schramm, Kshitij Wagh, Bette Korber, Michael S Seaman, Daniel C Douek, Barton F Haynes, Daniel W Kulp, Mario Roederer, Beatrice H Hahn, Peter D Kwong, George M Shaw

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引用次数: 0

Abstract

Broadly neutralizing antibodies (bNAbs) targeting the HIV-1 CD4-binding site (CD4bs) occur infrequently in macaques and humans and have not been reproducibly elicited in any outbred animal model. To address this challenge, we first isolated RHA10, an infection-induced rhesus bNAb with 51% breadth. The cryoelectron microscopy (cryo-EM) structure of RHA10 with the HIV-1 envelope (Env) resembled prototypic human CD4bs bNAbs with CDR-H3-dominated binding. Env-antibody co-evolution revealed transient elimination of two Env CD4bs-proximal glycans near the time of RHA10-lineage initiation, and these glycan-deficient Envs bound preferentially to early RHA10 intermediates, suggesting that glycan deletions in infecting SHIVs could induce CD4bs bNAbs. To test this hypothesis, we constructed SHIV.CH505 variants with CD4bs-proximal glycan deletions. Infection of 11 macaques resulted in accelerated CD4bs bNAb responses in 9 compared with 1 of 115 control macaques. Glycan hole-based immunofocusing coupled to Env-Ab co-evolution can consistently induce broad CD4bs responses in macaques and serve as a model for HIV vaccine design.

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瞬时聚糖屏蔽还原诱导shiv感染猕猴cd4结合位点广泛中和抗体。

针对HIV-1 cd4结合位点（CD4bs）的广泛中和抗体（bNAbs）在猕猴和人类中很少出现，并且在任何远交动物模型中都没有可重复性地被诱导出来。为了解决这一挑战，我们首先分离了RHA10，一种宽度为51%的感染诱导恒河猴bNAb。具有HIV-1包膜（Env）的RHA10的冷冻电镜（cryo-EM）结构类似于具有cdr - h3主导结合的原型人CD4bs bNAbs。Env抗体的共同进化表明，在RHA10谱系起始时，两种Env CD4bs近端聚糖被短暂消除，这些缺乏聚糖的Env优先结合早期RHA10中间产物，这表明感染shiv时的聚糖缺失可以诱导CD4bs bNAbs。为了验证这一假设，我们构建了SHIV。cd4bs -近端聚糖缺失的CH505变异。与115只对照猕猴中的1只相比，11只猕猴感染导致9只猕猴的CD4bs bNAb反应加速。甘聚糖空穴免疫聚焦与Env-Ab协同进化可以在猕猴中持续诱导广泛的CD4bs应答，并可作为HIV疫苗设计的模型。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.