Cale Evan M, Shen Chen-Hsiang, Olia Adam S, Radakovich Nathan A, Rawi Reda, Yang Yongping, Ambrozak David R, Bennici Anthony K, Chuang Gwo-Yu, Crooks Emma D, Driscoll Jefferson I, Lin Bob C, Louder Mark K, Madden Patrick J, Messina Michael A, Osawa Keiko, Stewart-Jones Guillaume B E, Verardi Raffaello, Vrakas Zoe, Xie Danielle, Zhang Baoshan, Binley James M, Connors Mark, Koup Richard A, Pierson Theodore C, Doria-Rose Nicole A, Kwong Peter D, Mascola John R, Gorman Jason
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
San Diego Biomedical Research Institute, San Diego, CA 92121, USA.
Cell Rep. 2024 Dec 24;43(12):115010. doi: 10.1016/j.celrep.2024.115010. Epub 2024 Dec 14.
Antibodies that target the gp120-gp41 interface of the HIV-1 envelope (Env) trimer comprise a commonly elicited category of broadly neutralizing antibodies (bNAbs). Here, we isolate and characterize VRC44, a bNAb lineage with up to 52% neutralization breadth. The cryoelectron microscopy (cryo-EM) structure of antibody VRC44.01 in complex with the Env trimer reveals binding to the same gp120-gp41 interface site of vulnerability as antibody 35O22 from a different HIV-1-infected donor. In addition to having similar angles of approach and extensive contacts with glycans N88 and N625, VRC44 and 35O22 derive from the same IGHV1-18 gene and share convergent mutations, indicating these two antibodies to be members of the only known highly glycan-dependent multidonor class. Strikingly, both lineages achieved almost 100% neutralization breadth against virus strains displaying high-mannose glycans. The high breadth and reproducible elicitation of VRC44 and 35O22 lineages validate germline-based methods of immunogen design for targeting the HIV-1 gp120-gp41 interface.
靶向HIV-1包膜（Env）三聚体gp120-gp41界面的抗体构成了一类常见的广泛中和抗体（bNAb）。在此，我们分离并表征了VRC44，这是一种具有高达52%中和广度的bNAb谱系。抗体VRC44.01与Env三聚体复合物的冷冻电镜（cryo-EM）结构显示，其与来自另一位HIV-1感染供体的抗体35O22一样，结合到相同的gp120-gp41界面易损位点。除了具有相似的接近角度以及与聚糖N88和N625广泛接触外，VRC44和35O22源自相同的IGHV1-18基因并共享趋同突变，这表明这两种抗体是唯一已知的高度依赖聚糖的多供体类别的成员。引人注目的是，这两个谱系对显示高甘露糖聚糖的病毒株均实现了近100%的中和广度。VRC44和35O22谱系的高广度和可重复诱导验证了基于种系的免疫原设计方法可用于靶向HIV-1 gp120-gp41界面。
