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: 10160694
• 负责人: Marie Pancera
• 金额: $ 26.4万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10160694
• 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.

项目摘要/摘要 广泛中和抗体（BNAB）可能是HIV-1疫苗的重要组成部分。艾滋病毒 - 1包膜（Env）糖蛋白是BNAB的唯一靶标，一直是免疫原料设计的重点。然而 各种重组（REC）ENVS不显示与某些BNAB的推断种系（GL）的可检测结合， 例如VRC01级BNAB，这是该提案的重点。 rec Envs能够结合GLVRC01 当用作免疫原子时，BNAB已设计并诱导GLVRC01 BNAB的产生。 但是，这些新型免疫原不足以诱导GLVRC01级BNAB的成熟 广泛的中和形式。在这里，我们建议将新型试剂用作免疫原以指导开发 VRC01级bnabs的作者：1）用携带短聚糖的免疫原给敲击小鼠进行免疫敲击小鼠以评估 如果这些能够更有效地促进免疫反应，以适应HIV-1 Env Glycan Shield和 2）结合免疫学和生物物理（包括原子水平结构）的表征。我们 假设这样的免疫原子已经知道如何容纳短糖，因此更多 适合成熟。我们的初步数据表明，这种抗原与前体的结合增加了 GLVRC01样抗体。单克隆抗体（mAb）的测序以及结构信息 将提供有关动物与疫苗引诱的抗体之间相互作用的分子细节 免疫原生物：更好地了解新型疫苗吸收的mAb的靶向表位将有助于我们识别 未来免疫研究的最佳增强免疫原，从而指导HIV-1疫苗设计。