IAVI Neutralizing Antibody Center, Consortium for HIV/AIDS Vaccine Development (CHAVD), Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Duke University Human Vaccine Institute, Departments of Medicine and Surgery, Duke University School of Medicine, Durham, NC 27710, USA; Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery at Duke University, Durham, NC 27710, USA.
Cell Rep. 2021 Nov 2;37(5):109922. doi: 10.1016/j.celrep.2021.109922.
Recognition of N-linked glycan at residue N276 (glycan276) at the periphery of the CD4-binding site (CD4bs) on the HIV-envelope trimer is a formidable challenge for many CD4bs-directed antibodies. To understand how this glycan can be recognized, here we isolate two lineages of glycan276-dependent CD4bs antibodies. Antibody CH540-VRC40.01 (named for donor-lineage.clone) neutralizes 81% of a panel of 208 diverse strains, while antibody CH314-VRC33.01 neutralizes 45%. Cryo-electron microscopy (cryo-EM) structures of these two antibodies and 179NC75, a previously identified glycan276-dependent CD4bs antibody, in complex with HIV-envelope trimer reveal substantially different modes of glycan276 recognition. Despite these differences, binding of glycan276-dependent antibodies maintains a glycan276 conformation similar to that observed in the absence of glycan276-binding antibodies. By contrast, glycan276-independent CD4bs antibodies, such as VRC01, displace glycan276 upon binding. These results provide a foundation for understanding antibody recognition of glycan276 and suggest its presence may be crucial for priming immunogens seeking to initiate broad CD4bs recognition.
识别 HIV 包膜三聚体 CD4 结合位点（CD4bs）周围残基 N276 上的 N 连接聚糖（聚糖 276），是许多针对 CD4bs 的抗体面临的巨大挑战。为了了解这种聚糖如何被识别，我们在这里分离出两种依赖聚糖 276 的 CD4bs 抗体谱系。抗体 CH540-VRC40.01（以供体谱系克隆命名）中和了 208 种不同株系的面板中的 81%，而抗体 CH314-VRC33.01 中和了 45%。这两种抗体与之前鉴定的依赖聚糖 276 的 CD4bs 抗体 179NC75 与 HIV 包膜三聚体复合物的冷冻电镜（cryo-EM）结构揭示了聚糖 276 识别的截然不同模式。尽管存在这些差异，但依赖聚糖 276 的抗体的结合保持了与未结合聚糖 276 结合抗体时观察到的相似的聚糖 276 构象。相比之下，如 VRC01 等不依赖聚糖 276 的 CD4bs 抗体在结合时会取代聚糖 276。这些结果为理解抗体对聚糖 276 的识别提供了基础，并表明其存在可能对启动寻求广泛 CD4bs 识别的免疫原至关重要。
