HIV-1 vaccine-elicited antibodies target envelope glycans

HIV-1 疫苗引发的抗体靶向包膜聚糖

• 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
• 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

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.

项目摘要 HIV-1信封（ENV）糖蛋白的抗体识别受到压囊宿主聚糖的阻碍 那个覆盖env的表面。与Env Glycans相互作用的抗体有可能发展广泛的HIV- 1反应性和中和。但是，宿主聚糖的免疫原性很差，对 引起聚糖反应性中和抗体。在我们赠款的第一学期中，我们定义了一种新型的 中和HIV-1抗体结合了屏蔽HIV-1包膜的聚糖。这些抗体是 从多个接种的猕猴和猿猴免疫缺陷病毒感染的猕猴中分离出来。 这些抗体与已知的聚糖依赖性HIV-1抗体不同，暴露于形成I形的能力 和Y形的IgG分子，并通过重链变量形成的深腔与聚糖结合 地区。我们称这种类型的抗体Fab-二聚体聚糖（FDG）抗体，因为 Fabs产生了I形构象。当疫苗诱导的FDG抗体广泛中和HIV-1时 病毒糖基化仅限于MAN9GLCNAC2-这些糖基化称为I型FDG抗体。 II型FDG 抗体类似于I型，除了它们不需要MAN9GLCNAC2富集以谈判 引发抗体谱系的自体病毒。此外，感染的III型FDG抗体 猕猴与I型疫苗诱导的FDG抗体相比，与更多的糖基化位点结合，暴露于 HIV-1中和活性无关HIV-1包膜上存在的聚糖类型。科学前提 这项工作是FDG抗体HIV-1神经化宽度取决于抗体 识别多个ENV糖基化位点以及对每个ENV的潜水聚糖的抗体识别 糖基化位点。这项研究的目的是指导I型抗体亲和力成熟和选择 III型FDG抗体的FDG抗体。我们设计了结构和抗原模拟 这些抗体靶向的Env的糖基化区域，并在A上排列了该糖肽的24份 蛋白质纳米颗粒。我们建议将FDG抗体与血清表明的接种猕猴分离 它们的抗体正在形成III型，广泛中和FDG抗体（AIM 1）；确定 I型和III型FDG抗体之间的常见遗传或生化特征，有助于 神经化广度的发展（AIM 2）；并引起与Env的猕猴中的III型FDG抗体 最小的免疫原纳米颗粒（AIM 3）。这项工作很重要，因为它将定义可再现的途径 引起HIV-1广泛中和抗体，它将将滥交的聚糖识别定义为 FDG抗体发生中和宽度的机制。这种方法会产生很大的影响 在现场，它将展示一种诱导HIV-1 BNAB的替代疫苗方法 不需要靶向和牧羊的稀有抗体的罕见前体。