Immunogen Design for Induction of HIV distal gp41 broadly neutralizing antibodies

用于诱导 HIV 远端 gp41 广泛中和抗体的免疫原设计

• 批准号: 10132973
• 负责人: S. Munir ALAM
• 金额: $ 155.24万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-09 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10132973
• 关键词: Affinity; Animal Model; Animals; Antibodies; Antibody Affinity; Antibody Response; Antigen Receptors; Antigens; Autologous; B-Lymphocytes; Binding; Cell Lineage; Cellular biology; Clone Cells; Collaborations; Complex; Coupled; Cryoelectron Microscopy; Crystallization; Detection; Development; Directed Molecular Evolution; Distal; Genealogy; Goals; HIV; HIV vaccine; HIV-1; Hydrophobicity; Immune Tolerance; Immunization; Knock-in Mouse; Lead; Lipids; Macaca mulatta; Membrane; Membrane Lipids; Monoclonal Antibodies; Mus; Mutation; Pathway interactions; Physiological; Process; Proteins; Reagent; Regimen; Site-Directed Mutagenesis; Somatic Mutation; Structure; Surface; Testing; Vaccines; Virion; X-Ray Crystallography; Yeasts; base; computer program; design; expectation; information model; iterative design; member; mouse model; neutralizing antibody; novel; novel strategies; programs; vaccine development; ward

The overall objective is to develop immunogens that will initiate and select HIV-1 broad neutralizing antibody (bnAb) lineages directed to the distal membrane proximal external region (MPER) of HIV Env gp41. Distal gp41 MPER antibody types such as 10E8 and DH511 are desirable because they are among the most broad and potent bnAbs isolated. There are two strategies for bnAb immunogen design lineages. (1) Define bnAb clonal lineage genealogies, infer the bnAb unmutated common ancestor (UCA) and select autologous Envs that bind—termed B cell lineage immunogen design. (2) Structural-based design, using structures of sequential lineage Abs to design Envs that bind to bnAb lineage members. Here we propose to combine the strengths of both strategies to design immunogens that can initiate and induce distal MPER bnAbs. We will use the newly isolated DH511 lineage UCA, intermediate antibodies (IAs) and bnAbs as reagents upon which to design sequential immunogens that will select DH511-like precursors and lead to bnab development (Project 1, William Schief, PI), and to test these immunogens in physiologically relevant knock-in mouse model of bnAb development (Project 2 (Munir Alam, PI, Small Animal Models Core, Ming Tian, PI, Fred Alt, Co-I). A computational program, Antigen Receptor Mutation Analyzer for Detection of Low Likelihood Occurrences (ARMADiLLO) (Project 2) that allows for definition of the critical antibody somatic mutations to be induced will be used to determine key IAs that a successful vaccine will need to target. Overall Specific Aim 1. Define the key IAs and antibody somatic mutations that a successful vaccine will need to select to lead to distal MPER bnAb induction. (Projects 1 and 2) Overall Specific Aim 2. Design of germline targeting (GT) prime and boost immunogens that bind to the DH511 precursors and to key IAs and mature DH511 bnAbs in optimal affinities and can select the correct/desired IAs and bnAbs. (Project 1) Overall Specific Aim 3. Solve co-crystal and cryoEM structures of DH511 and DH511-like lineage antibodies with Env immunogens that move the lineage along the bnAb maturation pathway and enable design of additional immunogens to complete the induction of distal MPER bnAbs B cell lineages. (Project 1) Overall Specific Aim 4. Selection of optimal Env immunogens from immunizations of DH511 UCA and IA VH and VL knock-in mice. This will be accomplished by use of the novel DH511 UCA VHDJH-rearranging mouse recently developed by Ming Tian and Fred Alt at Harvard. (Small Animal Core; Projects 1 and 2). This collaboration of three leading academic teams in HIV vaccine immunogen design will bring together expertise in structure-based and lineage-based design, and will be a powerful approach to the problem of vaccine induction of disfavored antibody lineages in general and distal MPER bnAbs in particular.

总体目的是开发免疫原，从而启动抗烟草并选择HIV-1广泛中和抗体 （bnab）谱系载于HIV Env GP4​​1的远端膜外部区域（MPER） GP41 MPer抗体类型（例如10E8和DH511）是可取的，因为它们是最广泛的 有效的bnab是隔离的 克隆谱系家谱，推断BNAB未拆卸的共同祖先（UCA），然后选择自动学 ENV结合 - termed B细胞谱系免疫原设计。 序列谱系ABS设计为bnab谱系成员。 两种策略设计免疫原策略的优势 bnabs。 设计顺序不育元的试剂将选择类似DH511的前体并引导 BNAB开发（Project 1，William Schoolief，PI），并测试与生理学相关的免疫原子 BNAB开发的敲入小鼠模型（项目2（Munir Alam，Pi，小动物模型核心， 明天，pi，弗雷德·阿尔特（Fred Alt），co-i）。 允许定义关键抗体的可能性发生（Armadillo）（项目2） 要诱导的体细胞突变将确定成功的疫苗需要的关键 目标。 总体特定目的1。定义成功疫苗的关键IAS和抗体体细胞突变 需要选择远端MPER诱导（项目1和2） 总体特定目的2。菌根靶向（GT）素数的设计和增强的免疫原子与结合 DH511前体和关键的IAS和成熟的DH511 bnabs以最佳亲和力，可以选择您 正确/想要的是BNAB（项目1） 总体特定目的3。解决DH511和DH511样谱系的共晶和冷冻结构 具有ENV免疫原的抗体，沿BNAB成熟途径的谱系并启用 （项目1） 总体特定目的4。从DH511 UCA和IA的免疫中选择最佳ENV免疫原子 VH和VL敲击小鼠 小鼠最近在哈佛大学上由明天和弗雷德·弗雷德（Fred Fred Alt）开发（项目1和2）。 三个领先的HIV疫苗免疫原设计学术团队的合作将带来 在基于结构和基于谱系的设计方面的专业知识，将是一种强大的方法 通常，尤其是MPER BNAB的疫苗抗体疫苗指示问题。