Optimizing Humoral Responses to HIV-1 Env Vaccine Antigens

优化对 HIV-1 Env 疫苗抗原的体液反应

• 批准号: 10631900
• 负责人: GARNETT H KELSOE
• 金额: $ 88.55万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-07 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631900
• 关键词: Adjuvant; Affect; Affinity; Antibodies; Antibody Formation; Antibody Response; Antigen Receptors; Antigens; Appearance; Autologous; B-Cell Activation; B-Lymphocytes; Binding; Blood; Blood specimen; Cell Compartmentation; Cell Separation; Cells; Chronic; Cohort Studies; Development; Engineering; Environment; Exposure to; Genes; Genetic Transcription; HIV-1; Helper-Inducer T-Lymphocyte; Immunization; Immunize; Immunologics; Individual; Infection; Knock-in; Knock-in Mouse; Label; Link; Lymphocyte; Macaca mulatta; Maps; Measures; Memory B-Lymphocyte; Molecular; Mus; Mutation; Phenotype; Plasma Cells; Play; Polysaccharides; Probability; Proliferating; Role; Sampling; Secondary to; Serology; Serum; Specificity; Structure of germinal center of lymph node; T cell receptor repertoire sequencing; T-Lymphocyte; T-cell receptor repertoire; Tamoxifen; Vaccine Antigen; Vaccine Design; Vaccines; Variant; aspirate; cohort; longitudinal analysis; lymph nodes; mutant; neutralizing antibody; response; simian human immunodeficiency virus; single cell analysis; transcriptome; transcriptome sequencing; vaccine efficacy

Project Summary BCR affinity drives selection of mutations that increase potency and breadth in serum antibody (Ab), but also predisposes the fate choices of GC B cells towards terminal PC differentiation. We will study the role of BCR affinity in determining the fates of B cells exposed to serial immunizations or chronic SHIV infection to optimize vaccine efficacy. Parallel studies carried out in knock-in mice expressing the germline ancestor (UCA) of a V3 glycan bNAb lineage and in rhesus macaques (RMs) will merge lineage tracing of GC B and T cells with high throughput transcriptional analysis of individual lymphocytes to determine how and what immunological environments maximize the probability of eliciting broadly neutralizing antibody (bNAb) responses. We will use engineered Env vaccine antigens (Ags) to optimize the return of Bmem to secondary and tertiary GCs in BCR KI mice, and to determine how BCR affinity affects differentiation to the GC, Bmem and PC compartments. In SHIV infected RMs, we will in parallel map BCR affinities associated with nascent bNAb production and determine the effects of prior immunization with selected Env vaccines on subsequent, homologous or heterologous infection.

项目概要 BCR 亲和力驱动突变的选择，从而增加血清抗体 (Ab) 的效力和广度，但也 使 GC B 细胞的命运选择倾向于终末 PC 分化。我们将研究BCR的作用 亲和力决定暴露于连续免疫或慢性 SHIV 感染的 B 细胞的命运，以优化 疫苗功效。在表达 V3 种系祖先 (UCA) 的敲入小鼠中进行的平行研究 聚糖 bNAb 谱系和恒河猴 (RM) 将合并 GC B 和 T 细胞的谱系追踪，具有高 对单个淋巴细胞进行通量转录分析，以确定免疫学的方式和内容 环境最大限度地提高了引发广泛中和抗体（bNAb）反应的可能性。我们将使用 工程化 Env 疫苗抗原 (Ags) 以优化 BCR 中 Bmem 向二级和三级 GC 的返回 KI 小鼠，并确定 BCR 亲和力如何影响 GC、Bmem 和 PC 区室的分化。在 SHIV 感染的 RM，我们将同时绘制与新生 bNAb 产生相关的 BCR 亲和力， 确定先前使用选定的 Env 疫苗进行免疫接种对后续、同源或 异源感染。