Optimizing Humoral Responses to HIV-1 Env Vaccine Antigens

项目摘要 Bcr亲和力推动了突变的选择，这些突变不仅增加了血清抗体的效力和广度，而且还 使GC B细胞的命运选择倾向于PC终末分化。我们将研究BCR的作用 亲和力在确定连续免疫或慢性SHV感染后B细胞命运中的优化 疫苗的效力。在表达V3生殖系祖先(UCA)的敲除小鼠中进行的平行研究 Glycan bNAb谱系和恒河猴(RMS)将合并GC B和T细胞的谱系追踪与高 通过对单个淋巴细胞的转录分析来确定免疫方式和免疫方式 环境使激发广谱中和抗体(BNAb)反应的可能性最大化。我们将使用 工程化环境疫苗抗原(AGS)优化Bmem向BCR中二、三级GCs的回归 并确定BCR亲和力如何影响向GC、Bmem和PC区的分化。在……里面 ，我们将平行地绘制与新生bNAb产生和bNAb产生相关的BCR亲和力 确定之前使用选定的环境疫苗接种对后续、同源或 异源感染。

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.