How precursor frequencies and antigen affinities impact interclonal B cell competition is a particularly relevant issue for candidate germline-targeting HIV vaccine designs because of the in vivo rarity of naive B cells that recognize broadly neutralizing epitopes. Knowing the frequencies and affinities of HIV-specific VRC01-class naive human B cells, we transferred B cells with germline VRC01 B cell receptors into congenic recipients to elucidate the roles of precursor frequency, antigen affinity, and avidity on B cell responses following immunization. All three factors were interdependently limiting for competitive success of VRC01-class B cells. In physiological high-affinity conditions using a multivalent immunogen, rare VRC01-class B cells successfully competed in germinal centers (GC), underwent extensive somatic hypermutation, and differentiated into memory B cells. The data reveal dominant influences of precursor frequency, affinity, and avidity for interclonal GC competition and indicate that germline-targeting immunogens can overcome these challenges with high-affinity multimeric designs.

前体频率和抗原亲和力如何影响克隆间B细胞竞争是针对候选种系靶向HIV疫苗设计的一个特别相关的问题，因为其体内存在很少能识别广泛中和的抗原决定簇的幼稚B细胞。知道HIV特异性VRC01类天真人类B细胞的频率和亲和力后，我们将具有种系VRC01 B细胞受体的B细胞转移到同类受体中，以阐明免疫后前体频率，抗原亲和力和亲和力对B细胞反应的作用。所有这三个因素相互依赖地限制了VRC01 B类细胞的竞争成功。在使用多价免疫原的生理高亲和力条件下，稀有的VRC01类B细胞在生发中心（GC）中成功竞争，经历了广泛的体细胞超突变，并分化为记忆B细胞。数据揭示了前体频率，亲和力，