Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
Science. 2019 Dec 6;366(6470). doi: 10.1126/science.aax4380. Epub 2019 Oct 31.
Vaccine induction of broadly neutralizing antibodies (bnAbs) to HIV remains a major challenge. Germline-targeting immunogens hold promise for initiating the induction of certain bnAb classes; yet for most bnAbs, a strong dependence on antibody heavy chain complementarity-determining region 3 (HCDR3) is a major barrier. Exploiting ultradeep human antibody sequencing data, we identified a diverse set of potential antibody precursors for a bnAb with dominant HCDR3 contacts. We then developed HIV envelope trimer-based immunogens that primed responses from rare bnAb-precursor B cells in a mouse model and bound a range of potential bnAb-precursor human naïve B cells in ex vivo screens. Our repertoire-guided germline-targeting approach provides a framework for priming the induction of many HIV bnAbs and could be applied to most HCDR3-dominant antibodies from other pathogens.
疫苗诱导针对 HIV 的广泛中和抗体（bnAbs）仍然是一个主要挑战。针对种系的免疫原有望启动某些 bnAb 类别的诱导；然而，对于大多数 bnAbs 而言，强烈依赖抗体重链互补决定区 3（HCDR3）是一个主要障碍。利用超深度人类抗体测序数据，我们鉴定了具有主导 HCDR3 接触的 bnAb 的多种潜在抗体前体。然后，我们开发了基于 HIV 包膜三聚体的免疫原，该免疫原在小鼠模型中刺激了稀有 bnAb 前体 B 细胞的反应，并在体外筛选中结合了一系列潜在的 bnAb 前体人类幼稚 B 细胞。我们的库指导种系靶向方法为诱导许多 HIV bnAbs 的诱导提供了框架，并且可以应用于来自其他病原体的大多数 HCDR3 主导抗体。
