Scientific Core Two

科学核心二

• 批准号: 10589644
• 负责人: Marie Pancera
• 金额: $ 48.47万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-30 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589644
• 关键词: Antibodies; Antibody Formation; Antibody Response; Antigens; B-Lymphocytes; Binding; Biochemical; Complement 4b; Complex; Cryoelectron Microscopy; Crystallization; Cyclic GMP; Electron Microscopy Facility; Enzyme-Linked Immunosorbent Assay; Epitopes; Glycoproteins; HIV-1; HIV-1 vaccine; Human; Immunization; In Vitro; Knock-in Mouse; Mammalian Cell; Maps; Membrane; Messenger RNA; Methodology; Methods; Monoclonal Antibodies; Production; RNA vaccine; Reagent; Recombinant Antibody; Recombinant Proteins; Recombinants; Resolution; Robot; Sarna; Structure; Universities; Vaccines; Validation; Washington; X-Ray Crystallography; design; env Gene Products; env Glycoproteins; interest; manufacture; nanoparticle; neutralizing antibody; protein complex; response

PROJECT SUMMARY/ABSTRACT Broadly neutralizing antibodies are likely to be an important component of an HIV-1 vaccine. The HIV-1 Envelope (Env) glycoprotein is the sole target of neutralizing antibodies 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 our IPCAVD project. Rec Envs capable of binding glVRC01 bNAbs have been designed and induced the production of glVRC01 bNAbs when used as immunogens. In this IPCAVD, we propose to determine if self-amplifying (sa) mRNA expressing our germline- targeting 426c.Mod.Core prime and HxB2.WT.Core boost immunogens, expressed either as secreted nanoparticles (-C4b) or membrane-anchored (gp160ΔCT), will initiate the maturation of VRC01 B cell response in humans. The Scientific Core Two will provide high quality reagents to Scientific Projects One and Two and Scientific Core One of this IPCAVD as well as structural information on selected vaccine-elicited Mab of interest in complex with their antigens, to delineate their epitopes. This information will help us to better understand the B cell response elicited by the saRNA constructs compared to rec Env immunogens.

项目总结/摘要 广泛中和抗体可能是HIV-1疫苗的重要组成部分。HIV-1包膜 (Env)糖蛋白是中和抗体的唯一靶标，并且一直是免疫原设计的焦点。然而 不同的重组（rec）Env不显示与某些bNAb的推断的种系（g1）的可检测的结合， 例如VRC 01级bNAb，这是我们IPCAVD项目的重点。Rec Envs能够结合 已经设计了glVRC 01 bNAb，并且当用作载体时诱导glVRC 01 bNAb的产生。 免疫原在这个IPCAVD中，我们建议确定表达我们的生殖系的自扩增（sa）mRNA- 靶向426c.Mod.Core初免和HxB2.WT. Core加强免疫原，其表达为分泌型 纳米颗粒（-C4 B）或膜锚定的（gp 160 ΔCT）将启动VRC 01 B细胞应答的成熟 在人类身上。科学核心二号将为科学项目一号和二号提供高质量的试剂， 该IPCAVD之一以及所选疫苗诱导的感兴趣Mab的结构信息 与它们的抗原复合，以描绘它们的表位。这些信息将有助于我们更好地了解 与rec Env免疫原相比，由saRNA构建体引发的B细胞应答。