Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
Department of Biology, Stanford University, Stanford, CA, USA.
Nat Commun. 2022 Oct 17;13(1):6123. doi: 10.1038/s41467-022-33860-2.
BG24, a VRC01-class broadly neutralizing antibody (bNAb) against HIV-1 Env with relatively few somatic hypermutations (SHMs), represents a promising target for vaccine strategies to elicit CD4-binding site (CD4bs) bNAbs. To understand how SHMs correlate with BG24 neutralization of HIV-1, we report 4.1 Å and 3.4 Å single-particle cryo-EM structures of two inferred germline (iGL) BG24 precursors complexed with engineered Env-based immunogens lacking CD4bs N-glycans. Structures reveal critical Env contacts by BG24 and identify antibody light chain structural features that impede Env recognition. In addition, biochemical data and cryo-EM structures of BG24 variants bound to Envs with CD4bs glycans present provide insights into N-glycan accommodation, including structural modes of light chain adaptations in the presence of the N276 glycan. Together, these findings reveal Env regions critical for germline antibody recognition and potential sites to alter in immunogen design.
BG24 是一种针对 HIV-1 包膜的 VRC01 类广谱中和抗体（bNAb），其体细胞超突变（SHM）相对较少，代表了一种有前途的疫苗策略靶点，可以诱导 CD4 结合位点（CD4bs）bNAb。为了了解 SHM 如何与 BG24 对 HIV-1 的中和作用相关，我们报告了两个推断的种系（iGL）BG24 前体与缺乏 CD4bs N-聚糖的工程化基于 Env 的免疫原复合物的 4.1Å 和 3.4Å 单颗粒冷冻电镜结构。结构揭示了 BG24 的关键 Env 接触，并确定了阻碍 Env 识别的抗体轻链结构特征。此外，结合了带有 CD4bs 聚糖的 Env 的 BG24 变体的生化数据和冷冻电镜结构提供了对 N-聚糖容纳的深入了解，包括在存在 N276 聚糖的情况下轻链适应的结构模式。总之，这些发现揭示了种系抗体识别的关键 Env 区域和免疫原设计中可能改变的潜在位点。
