Potent and broad HIV-1 neutralization in fusion peptide-primed SHIV-infected macaques

Affiliations

• Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
• Department of Biochemistry and Molecular Biophysics and Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA; Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
• Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
• Microscopy Unit, Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA.
• Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.
• Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
• Vaccine Research Center Electron Microscopy Unit, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD 21702, USA.
• Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Modex Therapeutics Inc., Natick, MA 01760, USA.
• Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Department of Biochemistry and Molecular Biophysics and Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA; Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA. Electronic address: pdkwong@nih.gov.

PMID:  39471811  DOI: 10.1016/j.cell.2024.10.003

Abstract

An antibody-based HIV-1 vaccine will require the induction of potent cross-reactive HIV-1-neutralizing responses. To demonstrate feasibility toward this goal, we combined vaccination targeting the fusion-peptide site of vulnerability with infection by simian-human immunodeficiency virus (SHIV). In four macaques with vaccine-induced neutralizing responses, SHIV infection boosted plasma neutralization to 45%-77% breadth (geometric mean 50% inhibitory dilution [ID50] ∼100) on a 208-strain panel. Molecular dissection of these responses by antibody isolation and cryo-electron microscopy (cryo-EM) structure determination revealed 15 of 16 antibody lineages with cross-clade neutralization to be directed toward the fusion-peptide site of vulnerability. In each macaque, isolated antibodies from memory B cells recapitulated the plasma-neutralizing response, with fusion-peptide-binding antibodies reaching breadths of 40%-60% (50% inhibitory concentration [IC50] < 50 μg/mL) and total lineage-concentrations estimates of 50-200 μg/mL. Longitudinal mapping indicated that these responses arose prior to SHIV infection. Collectively, these results provide in vivo molecular examples for one to a few B cell lineages affording potent, broadly neutralizing plasma responses.

基于抗体的 HIV-1 疫苗需要诱导强效的HIV-1交叉反应的中和抗体。为了证明实现这一目标的可行性，我们将针对融合肽易感位点的疫苗接种与SHIV感染相结合。在四只具有疫苗诱导中和反应的猕猴中，SHIV 感染将血浆中和率提高到了 45%-77% 的广度（几何平均 50% 抑制性稀释 [ID50] ∼100）。通过抗体分离和低温电子显微镜（cryo-EM）结构测定对这些反应进行分子剖析后发现，在16种具有跨族中和作用的抗体系中，有15种是针对融合肽的易感部位的。在每只猕猴体内，从记忆B细胞中分离出的抗体重现了血浆中和反应，融合肽结合抗体的广度达到40%-60%（50%抑制浓度[IC50] < 50 μg/mL），总的系谱浓度估计为50-200 μg/mL。纵向映射表明，这些反应是在感染 SHIV 之前产生的。总之，这些结果提供了一个到几个B细胞系产生强效、广泛中和血浆反应的体内分子实例。

关键词：HIV-1，SHIV，中和抗体，疫苗，试剂盒，佰乐博，佰乐博生物