HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen.
HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen.
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DOI：
10.1126/science.aad9195
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发表时间：
2016-03-25
期刊：
影响因子：
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通讯作者：
Schief WR
中科院分区：
文献类型：
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作者：
Jardine JG;Kulp DW;Havenar-Daughton C;Sarkar A;Briney B;Sok D;Sesterhenn F;Ereño-Orbea J;Kalyuzhniy O;Deresa I;Hu X;Spencer S;Jones M;Georgeson E;Adachi Y;Kubitz M;deCamp AC;Julien JP;Wilson IA;Burton DR;Crotty S;Schief WR
诱导广泛中和抗体 (bnAb) 是 HIV 疫苗的主要目标。种系靶向免疫原旨在通过激活 bnAb 种系前体 B 细胞来启动 bnAb 诱导。尚未解决的关键挑战是确定 bnAb 前体幼稚 B 细胞是否结合种系靶向免疫原，并在人体中以足够的频率发生，以实现可靠的疫苗反应。我们采用深度突变扫描和多靶点优化来开发针对多种 VRC01 类 bnAb 的种系靶向免疫原 (eOD-GT8)。然后，我们使用免疫原从未感染 HIV 的捐赠者中分离出 VRC01 类前体幼稚 B 细胞。真正的 VRC01 类前体的频率、其结构及其 eOD-GT8 亲和力支持该免疫原作为候选人类疫苗初选。这些方法可应用于其他类别的 HIV bnAb 和其他病原体抗体的种系靶向。
Induction of broadly neutralizing antibodies (bnAbs) is a major HIV vaccine goal. Germline-targeting immunogens aim to initiate bnAb induction by activating bnAb germline precursor B cells. Critical unmet challenges are to determine whether bnAb precursor naïve B cells bind germline-targeting immunogens and occur at sufficient frequency in humans for reliable vaccine responses. We employed deep mutational scanning and multi-target optimization to develop a germline-targeting immunogen (eOD-GT8) for diverse VRC01-class bnAbs. We then used the immunogen to isolate VRC01-class precursor naïve B cells from HIV-uninfected donors. Frequencies of true VRC01-class precursors, their structures, and their eOD-GT8 affinities support this immunogen as a candidate human vaccine prime. These methods could be applied to germline targeting for other classes of HIV bnAbs and for Abs to other pathogens.