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.

项目摘要 BCR亲和力驱动突变的选择，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 在确定暴露于系列免疫或慢性SHIV感染的B细胞的命运中的亲和力，以优化 疫苗功效。在表达V3的种系祖先（UCA）的敲入小鼠中进行的平行研究 聚糖bNA B谱系和在恒河猴（RM）中将合并GC B和T细胞的谱系追踪， 单个淋巴细胞的通量转录分析，以确定如何以及 环境最大化引发广泛中和抗体（bNAb）应答的可能性。我们将使用 工程化Env疫苗抗原（Ags），以优化Bmem返回BCR中的二级和三级GC KI小鼠，并确定BCR亲和力如何影响分化为GC，BCR和PC隔室。在 在SHIV感染的RM中，我们将平行绘制与新生bNAb产生相关的BCR亲和力， 确定先前用选定的Env疫苗免疫对随后的同源或 异种感染