Structure-Based Designs of HIV-1 Immunogens Targeting Germline Precursors of Broadly Neutralizing Antibodies

针对广泛中和抗体种系前体的 HIV-1 免疫原的基于结构的设计

• 批准号: 10374164
• 负责人: Marie Pancera
• 金额: $ 22万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-17 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374164
• 关键词: Affinity; Animals; Antibodies; Antigens; B-Lymphocytes; Binding; Biophysics; Bypass; Cells; Clinical Trials; Clone Cells; Complex; Data; Development; Engineering; Enzyme-Linked Immunosorbent Assay; Epitopes; Family; Future; Genes; Genetic; Glycoproteins; Growth; HIV Envelope Protein gp120; HIV-1; HIV-1 vaccine; Immune response; Immunization; Immunize; Immunologics; Knock-in; Knock-in Mouse; Molecular; Monoclonal Antibodies; Polysaccharides; Positioning Attribute; Production; Property; Reagent; Recombinants; Research; Secondary Immunization; Serology; Site; Specific qualifier value; Spleen; Structure; Testing; Vaccine Design; Vaccines; Variant; Viral; Virus; Work; base; design; design and construction; improved; interest; neutralizing antibody; novel; novel vaccines

PROJECT SUMMARY/ABSTRACT Broadly neutralizing antibodies (bNAbs) are likely to be an important component of an HIV-1 vaccine. The HIV- 1 Envelope (Env) glycoprotein is the sole target of bNAbs and has been a focus of immunogen designs. Yet diverse recombinant (rec) Envs do not display detectable binding to the inferred germline (gl) of certain bNAbs, such as the VRC01-class bNAbs, which are the focus of this proposal. Rec Envs capable of binding glVRC01 bNAbs have been designed and induced the production of glVRC01 bNAbs when used as immunogens. However, these novel immunogens are not sufficient to induce the maturation of glVRC01-class bNAbs to their broad neutralization forms. Here we propose to use novel reagents as immunogens to guide the development of VRC01-class bNAbs by: 1) immunizing knock-in mice with immunogens harboring short glycans to evaluate if these could more efficiently prime immune responses that will accommodate the HIV-1 Env glycan shield and 2) combining immunological and biophysical (including atomic level structures) characterization. We hypothesize that such immunogens will already know how to accommodate short glycans and thus be more amenable to maturation. Our preliminary data show that such antigen has increased binding to precursors glVRC01-like antibodies. The sequencing of monoclonal antibodies (mAbs) along with structural information will provide molecular details on the interactions between the vaccine-elicited antibodies from animals and the immunogens: better understanding the epitopes targeted by the novel vaccine-elicited mAbs will help us identify the best boost immunogen for future immunizations studies and thus guide HIV-1 vaccine design.

项目总结/文摘