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: 10219934
• 负责人: KEVIN O SAUNDERS
• 金额: $ 78.98万
• 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/10219934
• 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.

项目总结