Germline-targeting HIV vaccination induces neutralizing antibodies to the CD4 binding site

IF 17.6 1区医学 Q1 IMMUNOLOGY

Science Immunology Pub Date : 2024-08-30 DOI:10.1126/sciimmunol.adk9550

Tom G. Caniels, Max Medina-Ramìrez, Shiyu Zhang, Sven Kratochvil, Yuejiao Xian, Ja-Hyun Koo, Ronald Derking, Jakob Samsel, Jelle van Schooten, Simone Pecetta, Edward Lamperti, Meng Yuan, María Ríos Carrasco, Iván del Moral Sánchez, Joel D. Allen, Joey H. Bouhuijs, Anila Yasmeen, Thomas J. Ketas, Jonne L. Snitselaar, Tom P. L. Bijl, Isabel Cuella Martin, Jonathan L. Torres, Albert Cupo, Lisa Shirreff, Kenneth Rogers, Rosemarie D. Mason, Mario Roederer, Kelli M. Greene, Hongmei Gao, Catarina Mendes Silva, Isabel J. L. Baken, Ming Tian, Frederick W. Alt, Bali Pulendran, Michael S. Seaman, Max Crispin, Marit J. van Gils, David C. Montefiori, Adrian B. McDermott, François J. Villinger, Richard A. Koup, John P. Moore, Per Johan Klasse, Gabriel Ozorowski, Facundo D. Batista, Ian A. Wilson, Andrew B. Ward, Rogier W. Sanders

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Abstract

Eliciting potent and broadly neutralizing antibodies (bnAbs) is a major goal in HIV-1 vaccine development. Here, we describe how germline-targeting immunogen BG505 SOSIP germline trimer 1.1 (GT1.1), generated through structure-based design, engages a diverse range of VRC01-class bnAb precursors. A single immunization with GT1.1 expands CD4 binding site (CD4bs)–specific VRC01-class B cells in knock-in mice and drives VRC01-class maturation. In nonhuman primates (NHPs), GT1.1 primes CD4bs-specific neutralizing serum responses. Selected monoclonal antibodies (mAbs) isolated from GT1.1-immunized NHPs neutralize fully glycosylated BG505 virus. Two mAbs, 12C11 and 21N13, neutralize subsets of diverse heterologous neutralization-resistant viruses. High-resolution structures revealed that 21N13 targets the same conserved residues in the CD4bs as VRC01-class and CH235-class bnAbs despite its low sequence similarity (~40%), whereas mAb 12C11 binds predominantly through its heavy chain complementarity-determining region 3. These preclinical data underpin the ongoing evaluation of GT1.1 in a phase 1 clinical trial in healthy volunteers.

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基因靶向艾滋病毒疫苗可诱导 CD4 结合位点的中和抗体

诱导强效广谱中和抗体（bnAbs）是 HIV-1 疫苗开发的主要目标。在这里，我们描述了通过基于结构设计产生的种系靶向免疫原 BG505 SOSIP 种系三聚体 1.1 (GT1.1)如何与多种 VRC01 级 bnAb 前体发生作用。在基因敲入小鼠中，GT1.1 的单次免疫可扩增 CD4 结合位点（CD4bs）特异性 VRC01 级 B 细胞，并促进 VRC01 级的成熟。在非人灵长类动物（NHPs）中，GT1.1可激发CD4bs特异性中和血清反应。从免疫了 GT1.1 的 NHPs 中分离出的部分单克隆抗体（mAbs）能中和完全糖基化的 BG505 病毒。两种 mAbs（12C11 和 21N13）能中和多种异源中和抗性病毒的子集。高分辨率结构显示，尽管 21N13 与 VRC01 级和 CH235 级 bnAbs 的序列相似度较低（约 40%），但其靶向 CD4bs 中相同的保守残基，而 mAb 12C11 则主要通过其重链互补决定区 3 结合。这些临床前数据为 GT1.1 目前在健康志愿者中进行的 1 期临床试验评估提供了依据。

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

Science Immunology Immunology and Microbiology-Immunology

CiteScore

32.90

自引率

2.00%

发文量

183

期刊介绍： Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.

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