Virus-like Particles Identify an HIV V1V2 Apex-Binding Neutralizing Antibody that Lacks a Protruding Loop

Most HIV-1-specific neutralizing antibodies isolated to date exhibit unusual characteristics that complicate their elicitation. Neutralizing antibodies that target the V1V2 apex of the HIV-1 envelope (Env) trimer feature unusually long protruding loops, which enable them to penetrate the HIV-1 glyca...

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Bibliographic Details
Published in:Immunity (Cambridge, Mass.) Mass.), 2017-05, Vol.46 (5), p.777-791.e10
Main Authors: Cale, Evan M., Gorman, Jason, Radakovich, Nathan A., Crooks, Ema T., Osawa, Keiko, Tong, Tommy, Li, Jiaqi, Nagarajan, Raju, Ozorowski, Gabriel, Ambrozak, David R., Asokan, Mangai, Bailer, Robert T., Bennici, Anthony K., Chen, Xuejun, Doria-Rose, Nicole A., Druz, Aliaksandr, Feng, Yu, Joyce, M. Gordon, Louder, Mark K., O’Dell, Sijy, Oliver, Courtney, Pancera, Marie, Connors, Mark, Hope, Thomas J., Kepler, Thomas B., Wyatt, Richard T., Ward, Andrew B., Georgiev, Ivelin S., Kwong, Peter D., Mascola, John R., Binley, James M.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Antibodies
Antibodies, Neutralizing - chemistry
Antibodies, Neutralizing - immunology
Antibodies, Neutralizing - metabolism
antibody
B cell ontogeny
B-Lymphocytes - immunology
B-Lymphocytes - metabolism
BASIC BIOLOGICAL SCIENCES
Binding Sites
bnAb
CDRH3
Complementarity Determining Regions - chemistry
Complementarity Determining Regions - immunology
Crystal structure
env Gene Products, Human Immunodeficiency Virus - immunology
glycan shield
HIV
HIV Antibodies - chemistry
HIV Antibodies - immunology
HIV Antibodies - metabolism
HIV Envelope Protein gp120 - chemistry
HIV Envelope Protein gp120 - immunology
HIV Envelope Protein gp120 - metabolism
HIV Infections - immunology
HIV Infections - virology
HIV-1 - immunology
Human immunodeficiency virus
Humans
Immunoglobulins
Lymphocytes B
Models, Molecular
NAb
neutralization
Peptide Fragments - chemistry
Peptide Fragments - immunology
Peptide Fragments - metabolism
Phylogeny
Plasmids
Probes
Protein Binding
Protein Conformation
Protein Interaction Domains and Motifs
Protein Multimerization
Recombination
trimer
V1V2
vaccine-design template
Vaccines
Vaccines, Virus-Like Particle - chemistry
Vaccines, Virus-Like Particle - immunology
Vaccines, Virus-Like Particle - metabolism
Virus-like particles
Viruses
VLP
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Summary:Most HIV-1-specific neutralizing antibodies isolated to date exhibit unusual characteristics that complicate their elicitation. Neutralizing antibodies that target the V1V2 apex of the HIV-1 envelope (Env) trimer feature unusually long protruding loops, which enable them to penetrate the HIV-1 glycan shield. As antibodies with loops of requisite length are created through uncommon recombination events, an alternative mode of apex binding has been sought. Here, we isolated a lineage of Env apex-directed neutralizing antibodies, N90-VRC38.01-11, by using virus-like particles and conformationally stabilized Env trimers as B cell probes. A crystal structure of N90-VRC38.01 with a scaffolded V1V2 revealed a binding mode involving side-chain-to-side-chain interactions that reduced the distance the antibody loop must traverse the glycan shield, thereby facilitating V1V2 binding via a non-protruding loop. The N90-VRC38 lineage thus identifies a solution for V1V2-apex binding that provides a more conventional B cell pathway for vaccine design. •VLPs and stabilized Env trimers identify HIV-1-neutralizing N90-VRC38 Ab lineage•Co-crystal structure of Ab N90-VRC38.01 with scaffolded V1V2-Env apex•N90-VRC38 lineage targets the apex of HIV-1 Env trimer with non-protruding loops•New mechanism of Ab:trimer-apex binding informs V1V2 vaccine strategies To date, long recognition loops have been a hallmark of apex-targeting antibodies. Cale et al. identify a lineage of HIV-1-neutralizing antibodies that target the envelope trimer apex. The N90-VRC38 lineage uses a loop of average length—a feature that may make it a useful prototype for vaccine design.
ISSN:1074-7613
1097-4180
DOI:10.1016/j.immuni.2017.04.011