Multidonor analysis reveals structural elements, genetic determinants, and maturation pathway for HIV-1 neutralization by VRC01-class antibodies.
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.
Zhou, T; Zhu, J; Wu, X; Moquin, S; Zhang, B; Acharya, P; Georgiev, IS; Altae-Tran, HR; Chuang, G-Y; Joyce, MG; Kwon, YD; Longo, NS; Louder, MK; Luongo, T; McKee, K; Schramm, CA; Skinner, J; Yang, Y; Yang, Z; Zhang, Z; Zheng, A; Bonsignori, M; Haynes, BF; Scheid, JF; Nussenzweig, MC; Simek, M; Burton, DR; Koff, WC; NISC Comparative Sequencing Program, ; Mullikin, JC; Connors, M; Shapiro, L; Nabel, GJ; Mascola, JR; Kwong, PD
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