HIV-1 vaccine-elicited antibodies target envelope glycans

HIV-1 疫苗引发的抗体靶向包膜聚糖

基本信息

批准号：
10082482
负责人：
KEVIN O SAUNDERS
金额：
$ 81.72万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10082482
关键词：
Affinity Amino Acids Animal Model Antibodies Antibody Affinity Antibody Binding Sites Antibody Response Antigens Autologous B-Lymphocytes Binding Biochemical Biochemistry Categories Cells Dependence Development Dimerization Elements Epitopes Exhibits Genes Genetic Glycopeptides Glycoproteins Goals Grant HIV HIV Antibodies HIV-1 HIV-1 vaccine Heterogeneity Human Immune response Immune system Immunogenetics Immunoglobulin G Immunoglobulin Variable Region Infection Investigation Macaca Macaca mulatta Mannose Molecular Conformation Monoclonal Antibodies Phenotype Polysaccharides Primates Proteins Serum Shapes Site Structure Surface Testing Vaccinated Vaccination Vaccine Design Vaccines Viral Proteins Virus Work arm complementarity-determining region 3 design dimer env Gene Products glycosylation immunogenic inhibiting antibody innovation mannosyl(9)-N-acetylglucosamine2 nanoparticle neutralizing antibody neutralizing vaccine novel prevent simian human immunodeficiency virus sugar vaccine development

项目摘要

PROJECT SUMMARY Antibody recognition of the HIV-1 envelope (Env) glycoprotein is hindered by the densely-packed host glycans that coat the surface of Env. Antibodies that interact with Env glycans have the potential to develop broad HIV- 1 reactivity and neutralization. However, host glycans are poorly immunogenic, presenting a challenge for eliciting glycan-reactive neutralizing antibodies. In the first term of our grant, we defined a new type of neutralizing HIV-1 antibody that bound the glycans that shield the HIV-1 envelope. These antibodies were isolated from multiple vaccinated macaques and simian-human immunodeficiency virus-infected macaques. Distinct from known glycan-dependent HIV-1 antibodies, these antibodies exhibited the ability to form I-shaped and Y-shaped IgG molecules, and bound to glycans via a deep cavity formed by the heavy chain variable region. We termed this type of antibody Fab-dimerized glycan (FDG) antibodies, since the dimerization of the Fabs generated the I-shaped conformation. Vaccine-induced FDG antibodies broadly neutralize HIV-1 when the virus glycosylation is restricted to Man9GlcNAc2–these are termed Type I FDG antibodies. Type II FDG antibodies are similar to Type I, except they do not require Man9GlcNAc2 enrichment for neutralization of the autologous virus that initiated the antibody lineage. Additionally, Type III FDG antibodies from infected macaques bind to more glycosylation sites than Type I vaccine-induced FDG antibodies, and exhibit broad HIV-1 neutralizing activity irrespective of the type of glycan present on HIV-1 envelope. The scientific premise of this work is that the development of FDG antibody HIV-1 neutralization breadth is dependent upon antibody recognition of multiple Env glycosylation sites, and antibody recognition of diverse glycans at each Env glycosylation site. The goal of this study will be to guide antibody affinity maturation and selection from Type I FDG antibodies to Type III FDG antibodies. We have designed structural and antigenic mimics of the glycosylated region of Env targeted by these antibodies, and arrayed 24 copies of this glycopeptide on a protein nanoparticle. We propose to isolate FDG antibodies from vaccinated macaques whose serum suggests their antibodies are developing into Type III broadly neutralizing FDG antibodies (Aim 1); determine the common genetic or biochemical features between Type I and Type III FDG antibodies that contribute to the development of neutralization breadth (Aim 2); and elicit Type III FDG antibodies in macaques with Env minimal immunogen nanoparticles (Aim 3). This work is significant because it will define a path for reproducibly eliciting HIV-1 broadly neutralizing antibodies, and it will define promiscuous glycan recognition as the mechanism by which neutralization breadth occurs for FDG antibodies. This approach would have great impact on the field as it will demonstrate an alternative vaccine approach for the induction of HIV-1 bnAbs that does not require targeting and shepherding rare precursors of broadly neutralizing antibodies.

项目概要 HIV-1 包膜 (Env) 糖蛋白的抗体识别受到密集的宿主聚糖的阻碍覆盖在 Env 表面的抗体与 Env 聚糖相互作用，有可能发展出广泛的 HIV- 1 反应性和中和作用然而，宿主聚糖的免疫原性较差，这对免疫原性提出了挑战。在我们资助的第一期，我们定义了一种新型的聚糖反应性中和抗体。中和 HIV-1 抗体，结合保护 HIV-1 包膜的聚糖。从多种疫苗猕猴和感染猿-人类免疫缺陷病毒的猕猴中分离出来。与已知的聚糖依赖性 HIV-1 抗体不同，这些抗体表现出形成 I 形的能力和 Y 形 IgG 分子，并通过重链变量形成的深腔与聚糖结合我们将这种类型的抗体称为 Fab 二聚聚糖 (FDG) 抗体，因为其二聚化。当疫苗诱导的 FDG 抗体广泛中和 HIV-1 时，Fab 会产生 I 形构象。病毒糖基化仅限于 Man9GlcNAc2——这些被称为 I 型 FDG 抗体。抗体与 I 型抗体相似，但它们不需要 Man9GlcNAc2 富集来中和启动抗体谱系的自体病毒另外还有来自感染的 III 型 FDG 抗体。与 I 型疫苗诱导的 FDG 抗体相比，猕猴与更多的糖基化位点结合，并表现出广泛的 HIV-1 中和活性与 HIV-1 包膜上存在的聚糖类型无关科学前提。这项工作的重点是 FDG 抗体 HIV-1 中和广度的开发取决于抗体识别多个 Env 糖基化位点，以及抗体识别每个 Env 上的不同聚糖本研究的目标是指导 I 型抗体亲和力成熟和选择。 FDG 抗体针对 III 型 FDG 抗体，我们设计了该抗体的结构和抗原模拟物。这些抗体靶向的 Env 糖基化区域，并将该糖肽的 24 个拷贝排列在我们建议从血清显示的细菌猕猴中分离出 FDG 抗体。他们正在开发的抗体是 III 型广泛中和 FDG 抗体（目标 1）； I 型和 III 型 FDG 抗体之间的共同遗传或生化特征有助于开发中和广度（目标 2）；并用 Env 在猕猴中引发 III 型 FDG 抗体最小的免疫原纳米粒子（目标 3），这项工作意义重大，因为它将定义一条可重复的路径。引发 HIV-1 广泛中和抗体，并将混杂的聚糖识别定义为 FDG 抗体发生中和宽度的机制将产生巨大影响。它将展示一种诱导 HIV-1 bnAb 的替代疫苗方法不需要靶向和引导广泛中和抗体的稀有前体。