Multidonor analysis reveals structural elements, genetic determinants, and maturation pathway for HIV-1 neutralization by VRC01-class antibodies.

TitleMultidonor analysis reveals structural elements, genetic determinants, and maturation pathway for HIV-1 neutralization by VRC01-class antibodies.
Publication TypeJournal Article
Year of Publication2013
AuthorsZhou T, Zhu J, Wu X, Moquin S, Zhang B, Acharya P, Georgiev IS, Altae-Tran HR, Chuang G-Y, M Joyce G, Kwon YDo, 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, Mullikin JC, Connors M, Shapiro L, Nabel GJ, Mascola JR, Kwong PD
Corporate AuthorsNISC Comparative Sequencing Program
JournalImmunity
Volume39
Issue2
Pagination245-58
Date Published08/22/2013
ISSN1097-4180
KeywordsAmino Acid Sequence, Antibodies, Monoclonal, Antibodies, Neutralizing, B-Lymphocytes, Base Sequence, Crystallography, X-Ray, HIV Antibodies, HIV Envelope Protein gp120, HIV Infections, HIV-1, Humans, Leukocytes, Mononuclear, Molecular Sequence Data, Sequence Analysis, DNA
Abstract

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.

DOI10.1016/j.immuni.2013.04.012
Alternate JournalImmunity
PubMed ID23911655
Grant ListT32 AI070084 / AI / NIAID NIH HHS / United States
U19 AI067854 / AI / NIAID NIH HHS / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
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