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

Cale EM, Gorman J, Radakovich NA, Crooks ET, Osawa K, Tong T, Li J, Nagarajan R, Ozorowski G, Ambrozak DR, Asokan M, Bailer RT, Bennici AK, Chen X, Doria-Rose NA, Druz A, Feng Y, Joyce MG, Louder MK, O'Dell S, Oliver C, Pancera M, Connors M, Hope TJ, Kepler TB, Wyatt RT, Ward AB, Georgiev IS, Kwong PD, Mascola JR, Binley JM
Immunity. 2017 46 (5): 777-791.e10

PMID: 28514685 · PMCID: PMC5512451 · DOI:10.1016/j.immuni.2017.04.011

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.

Copyright © 2017 Elsevier Inc. All rights reserved.

MeSH Terms (19)

Amino Acid Sequence Antibodies, Neutralizing B-Lymphocytes Binding Sites Complementarity Determining Regions env Gene Products, Human Immunodeficiency Virus HIV-1 HIV Antibodies HIV Envelope Protein gp120 HIV Infections Humans Models, Molecular Peptide Fragments Phylogeny Protein Binding Protein Conformation Protein Interaction Domains and Motifs Protein Multimerization Vaccines, Virus-Like Particle

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