Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors

• Published in: Cell 2015-06, Vol.161 (6), p.1280-1292
• Main Authors: Zhou, Tongqing, Lynch, Rebecca M., Chen, Lei, Acharya, Priyamvada, Wu, Xueling, Doria-Rose, Nicole A., Joyce, M. Gordon, Lingwood, Daniel, Soto, Cinque, Bailer, Robert T., Ernandes, Michael J., Kong, Rui, Longo, Nancy S., Louder, Mark K., McKee, Krisha, O’Dell, Sijy, Schmidt, Stephen D., Tran, Lillian, Yang, Zhongjia, Druz, Aliaksandr, Luongo, Timothy S., Moquin, Stephanie, Srivatsan, Sanjay, Yang, Yongping, Zhang, Baoshan, Zheng, Anqi, Pancera, Marie, Kirys, Tatsiana, Georgiev, Ivelin S., Gindin, Tatyana, Peng, Hung-Pin, Yang, An-Suei, Mullikin, James C., Gray, Matthew D., Stamatatos, Leonidas, Burton, Dennis R., Koff, Wayne C., Cohen, Myron S., Haynes, Barton F., Casazza, Joseph P., Connors, Mark, Corti, Davide, Lanzavecchia, Antonio, Sattentau, Quentin J., Weiss, Robin A., West, Anthony P., Bjorkman, Pamela J., Scheid, Johannes F., Nussenzweig, Michel C., Shapiro, Lawrence, Mascola, John R., Kwong, Peter D.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Antibodies, Neutralizing - chemistry; Antibodies, Neutralizing - metabolism; Antibodies, Viral - chemistry; Antibodies, Viral - metabolism; B-Lymphocytes - immunology; CD4 Antigens - metabolism; Complementarity Determining Regions; Epitopes, B-Lymphocyte; HIV Envelope Protein gp120 - chemistry; HIV Envelope Protein gp120 - immunology; HIV Envelope Protein gp120 - metabolism; HIV-1 - physiology; Humans; Models, Molecular; Molecular Sequence Data; Sequence Alignment
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2015.05.007

The site on the HIV-1 gp120 glycoprotein that binds the CD4 receptor is recognized by broadly reactive antibodies, several of which neutralize over 90% of HIV-1 strains. To understand how antibodies achieve such neutralization, we isolated CD4-binding-site (CD4bs) antibodies and analyzed 16 co-crystal structures –8 determined here– of CD4bs antibodies from 14 donors. The 16 antibodies segregated by recognition mode and developmental ontogeny into two types: CDR H3-dominated and VH-gene-restricted. Both could achieve greater than 80% neutralization breadth, and both could develop in the same donor. Although paratope chemistries differed, all 16 gp120-CD4bs antibody complexes showed geometric similarity, with antibody-neutralization breadth correlating with antibody-angle of approach relative to the most effective antibody of each type. The repertoire for effective recognition of the CD4 supersite thus comprises antibodies with distinct paratopes arrayed about two optimal geometric orientations, one achieved by CDR H3 ontogenies and the other achieved by VH-gene-restricted ontogenies. [Display omitted] •Population-level analysis revealed only two types of effective CD4bs antibodies•Each type, CDR H3-dominated or VH-gene-restricted, had distinct ontogenies•Both types could neutralize effectively, each with an optimal angle of approach•Despite geometric similarities, paratope chemistries were extremely diverse A population-level analysis of antibodies that recognize the CD4-binding site on the HIV-1 gp120 glycoprotein, the target of some of the most potent and broadly neutralizing antibodies, defines structural geometries, binding chemistries, and developmental pathways of antibody recognition, providing a catalog from which to choose optimal templates for vaccine design.