Morris Daniel J, Gorman Jason, Zhou Tongqing, Lora Jinery, Connell Andrew J, Li Hui, Liu Weimin, Roark Ryan S, Campion Mary S, Carey John W, Habib Rumi, Li Yingying, Martella Christian L, Park Younghoon, Singh Ajay, Sowers Kirsten J, Teng I-Ting, Wang Shuyi, Chohan Neha, Ding Wenge, Lauer Craig, Lewis Emily, Mason Rosemarie D, Rando Juliette M, Peyton Lowrey, Schramm Chaim A, Wagh Kshitij, Korber Bette, Seaman Michael S, Douek Daniel C, Haynes Barton F, Kulp Daniel W, Roederer Mario, Hahn Beatrice H, Kwong Peter D, Shaw George M
Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA; Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
Cell Rep. 2025 Jun 24;44(6):115848. doi: 10.1016/j.celrep.2025.115848. Epub 2025 Jun 13.
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.
靶向HIV-1 CD4结合位点（CD4bs）的广泛中和抗体（bNAbs）在猕猴和人类中出现的频率很低，并且在任何远交动物模型中都未能被可重复诱导产生。为应对这一挑战，我们首先分离出RHA10，一种具有51%广度的感染诱导恒河猴bNAb。RHA10与HIV-1包膜（Env）的冷冻电镜（cryo-EM）结构类似于以互补决定区H3（CDR-H3）为主导结合的原型人类CD4bs bNAbs。Env-抗体共同进化显示，在RHA10谱系起始时，两个Env CD4bs近端聚糖会短暂消除，并且这些聚糖缺陷型Env优先与早期RHA10中间体结合，这表明感染性猿猴/人免疫缺陷病毒（SHIV）中的聚糖缺失可诱导CD4bs bNAbs。为验证这一假设，我们构建了具有CD4bs近端聚糖缺失的SHIV.CH505变体。11只猕猴感染后，9只猕猴的CD4bs bNAb反应加速，而115只对照猕猴中只有1只出现这种情况。基于聚糖缺失的免疫聚焦结合Env-抗体共同进化能够在猕猴中持续诱导广泛的CD4bs反应，并可作为HIV疫苗设计的模型。
