Understanding how broadly neutralizing antibodies (bnAbs) to HIV envelope (Env) develop during natural infection can help guide the rational design of an HIV vaccine. Here, we described a bnAb lineage targeting the Env V2 apex and the Ab-Env co-evolution that led to development of neutralization breadth. The lineage Abs bore an anionic heavy chain complementarity-determining region 3 (CDRH3) of 25 amino acids, among the shortest known for this class of Abs, and achieved breadth with only 10% nucleotide somatic hypermutation and no insertions or deletions. The data suggested a role for Env glycoform heterogeneity in the activation of the lineage germline B cell. Finally, we showed that localized diversity at key V2 epitope residues drove bnAb maturation toward breadth, mirroring the Env evolution pattern described for another donor who developed V2-apex targeting bnAbs. Overall, these findings suggest potential strategies for vaccine approaches based on germline-targeting and serial immunogen design.

了解自然感染过程中针对HIV包膜（Env）的中和抗体（bnAbs）的发展程度如何，可以帮助指导HIV疫苗的合理设计。在这里，我们描述了针对Env V2顶点和Ab-Env共同进化的bnAb谱系，从而导致了中和广度的发展。世系的Abs带有25个氨基酸的阴离子重链互补决定区3（CDRH3），是此类Abs中已知的最短的，并且仅用10％的核苷酸体细胞超突变并且没有插入或缺失即可实现广谱。数据表明Env糖型异质性在谱系种系B细胞的激活中的作用。最后，我们发现关键V2表位残基的局部多样性驱使bnAb成熟趋向广度，反映了针对另一位捐助者的Env进化模式，该捐助者开发了针对bnAb的V2-apex。总体而言，这些发现表明了基于种系靶向和系列免疫原设计的疫苗方法的潜在策略。