Ganesh E Phad, Pradeepa Pushparaj, Karen Tran, Viktoriya Dubrovskaya, Monika Àdori, Paola Martinez-Murillo, Néstor Vázquez Bernat, Suruchi Singh, Gilman Dionne, Sijy O'Dell, Komal Bhullar, Sanjana Narang, Chiara Sorini, Eduardo J Villablanca, Christopher Sundling, Benjamin Murrell, John R Mascola, Lawrence Shapiro, Marie Pancera, Marcel Martin, Martin Corcoran, Richard T Wyatt, Gunilla B Karlsson Hedestam
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引用次数: 0
摘要
秩序井然的 HIV-1 包膜糖蛋白(Env)三聚体被优先用于临床评估,因此需要进一步了解免疫后诱导的 B 细胞反应是如何演变的。为了实现这一目标,我们用C族NFL三聚体对猕猴进行了原代强化,并从∼1,000个单次分选的Env特异性记忆B细胞中鉴定出了180个独特的抗体系。我们在从多个免疫分区和时间点生成的高通量重链(HC)序列(Rep-seq)数据中追踪了所有系谱,并将其中一些表达为单克隆抗体(mAbs)。我们的研究结果表明,大多数血系(包括第 2 级病毒中和血系)在增强后都出现了广泛的传播和高水平的体细胞超突变(SHM)。SHM在抗体互补决定区(CDRs)中最高,但在框架区(FRs),尤其是FR3中也出奇地高。我们的研究结果表明,免疫系统有能力同时亲和成熟大量的Env特异性B细胞系,从而支持使用由重复增强组成的方案来改进每一种Ab,即使是属于扩展较少的系。
Extensive dissemination and intraclonal maturation of HIV Env vaccine-induced B cell responses.
Well-ordered HIV-1 envelope glycoprotein (Env) trimers are prioritized for clinical evaluation, and there is a need for an improved understanding about how elicited B cell responses evolve following immunization. To accomplish this, we prime-boosted rhesus macaques with clade C NFL trimers and identified 180 unique Ab lineages from ∼1,000 single-sorted Env-specific memory B cells. We traced all lineages in high-throughput heavy chain (HC) repertoire (Rep-seq) data generated from multiple immune compartments and time points and expressed several as monoclonal Abs (mAbs). Our results revealed broad dissemination and high levels of somatic hypermutation (SHM) of most lineages, including tier 2 virus neutralizing lineages, following boosting. SHM was highest in the Ab complementarity determining regions (CDRs) but also surprisingly high in the framework regions (FRs), especially FR3. Our results demonstrate the capacity of the immune system to affinity-mature large numbers of Env-specific B cell lineages simultaneously, supporting the use of regimens consisting of repeated boosts to improve each Ab, even those belonging to less expanded lineages.