Multi-donor Analysis Reveals Structural Elements, Genetic Determinants, and Maturation Pathway for Effective HIV-1 Neutralization by VRCO1-class Antibodies

• Published in: Immunity (Cambridge, Mass.) Mass.), 2013-08, Vol.39 (2), p.245-258
• Main Authors: Zhou, Tongqing, Zhu, Jiang, Wu, Xueling, Moquin, Stephanie, Zhang, Baoshan, Acharya, Priyamvada, Georgiev, Ivelin S., Altae-Tran, Han R., Chuang, Gwo-Yu, Joyce, M. Gordon, Kwon, Young Do, Longo, Nancy S., Louder, Mark K., Luongo, Timothy, McKee, Krisha, Schramm, Chaim A., Skinner, Jeff, Yang, Yongping, Yang, Zhongjia, Zhang, Zhenhai, Zheng, Anqi, Bonsignori, Mattia, Haynes, Barton F., Scheid, Johannes F., Nussenzweig, Michel C., Simek, Melissa, Burton, Dennis R., Koff, Wayne C., Mullikin, James C., Connors, Mark, Shapiro, Lawrence, Nabel, Gary J., Mascola, John R., Kwong, Peter D.
• Format: Article
• Language: English
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2013.04.012

Antibodies of the VRC01 class neutralize HIV-1, arise in diverse HIV-1-infected donors, and are potential templates for an effective HIV-1 vaccine. However, the stochastic processes that generate repertoires in each individual of >10 12 antibodies make elicitation of specific antibodies uncertain. Here we determine the ontogeny of the VRC01 class by crystallography and next-generation sequencing. Despite antibody-sequence differences exceeding 50%, antibody-gp120 cocrystal structures reveal VRC01-class recognition to be remarkably similar. B cell transcripts indicate that VRC01-class antibodies require few specific genetic elements, suggesting that naive-B cells with VRC01-class features are generated regularly by recombination. Virtually all of these fail to mature, however, with only a few—likely one—ancestor B cell expanding to form a VRC01-class lineage in each donor. Developmental similarities in multiple donors thus reveal the generation of VRC01-class antibodies to be reproducible in principle, thereby providing a framework for attempts to elicit similar antibodies in the general population.