Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA, USA; Consortium for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA 92037, USA.
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA, USA.
Cell Rep. 2022 Mar 8;38(10):110485. doi: 10.1016/j.celrep.2022.110485.
Elicitation of HIV broadly neutralizing antibodies (bnAbs) is challenging because unmutated bnAb precursors are rare and seldom bind HIV envelope glycoprotein (Env) trimers. One strategy to initiate bnAb responses is to use germline-targeting (GT) immunogens with high affinity to bnAb-class precursor B cells and then shepherd affinity maturation with booster immunogens that successively look more like native Env. In a mouse model where the frequency of VRC01-precursor (VRC01) B cells mimics that of humans, we show that following a GT HIV Env trimer protein prime, VRC01-class B cells in the germinal center (GC) acquire high-affinity VRC01-class B cell somatic hypermutations (SHMs). Many GC-derived VRC01 antibodies robustly bind N276 glycan-deficient Env trimers and neutralize several N276 glycan-deficient tier 2 HIV strains. These results are encouraging for GT Env trimer vaccine designs and demonstrate accumulation of substantial SHMs, including deletions, uncommon point mutations, and functional bnAb features, after a single immunization.
HIV 广谱中和抗体（bnAb）的诱导具有挑战性，因为未突变的 bnAb 前体非常罕见，并且很少与 HIV 包膜糖蛋白（Env）三聚体结合。一种启动 bnAb 反应的策略是使用具有与 bnAb 类前体 B 细胞高亲和力的种系靶向（GT）免疫原，然后用增强免疫原进行亲和力成熟，这些增强免疫原依次更类似于天然Env。在一种模拟人类 VRC01 前体（VRC01）B 细胞频率的小鼠模型中，我们表明，在 GT HIV Env 三聚体蛋白引发后，生发中心（GC）中的 VRC01 类 B 细胞获得了高亲和力的 VRC01 类 B 细胞体细胞超突变（SHMs）。许多源自 GC 的 VRC01 抗体可强烈结合 N276 聚糖缺失的 Env 三聚体，并中和几种 N276 聚糖缺失的 2 级 HIV 株。这些结果令人鼓舞，为 GT Env 三聚体疫苗设计提供了依据，并证明在单次免疫后可积累大量的 SHMs，包括缺失、罕见点突变和功能性 bnAb 特征。
Nat Med. 2020-2-17
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