1. Particulate Array of Well-Ordered HIV Clade C Env Trimers Elicits Neutralizing Antibodies that Display a Unique V2 Cap Approach.
- Author
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Martinez-Murillo P, Tran K, Guenaga J, Lindgren G, Àdori M, Feng Y, Phad GE, Vázquez Bernat N, Bale S, Ingale J, Dubrovskaya V, O'Dell S, Pramanik L, Spångberg M, Corcoran M, Loré K, Mascola JR, Wyatt RT, and Karlsson Hedestam GB
- Subjects
- Antibodies, Neutralizing chemistry, Antibodies, Neutralizing metabolism, Epitope Mapping, Epitopes chemistry, Epitopes immunology, HIV Antibodies chemistry, HIV Antibodies metabolism, HIV-1 classification, HIV-1 genetics, Humans, Immunization, Models, Molecular, Molecular Docking Simulation, Peptide Fragments chemistry, Peptide Fragments metabolism, Protein Binding, Protein Conformation, Virion chemistry, Virion immunology, Virion ultrastructure, env Gene Products, Human Immunodeficiency Virus genetics, Antibodies, Neutralizing immunology, HIV Antibodies immunology, HIV-1 immunology, Peptide Fragments immunology, Protein Multimerization immunology, env Gene Products, Human Immunodeficiency Virus chemistry, env Gene Products, Human Immunodeficiency Virus immunology
- Abstract
The development of soluble envelope glycoprotein (Env) mimetics displaying ordered trimeric symmetry has ushered in a new era in HIV-1 vaccination. The recently reported native, flexibly linked (NFL) design allows the generation of native-like trimers from clinical isolates at high yields and homogeneity. As the majority of infections world-wide are of the clade C subtype, we examined responses in non-human primates to well-ordered subtype C 16055 trimers administered in soluble or high-density liposomal formats. We detected superior germinal center formation and enhanced autologous neutralizing antibodies against the neutralization-resistant (tier 2) 16055 virus following inoculation of liposome-arrayed trimers. Epitope mapping of the neutralizing monoclonal antibodies (mAbs) indicated major contacts with the V2 apex, and 3D electron microscopy reconstructions of Fab-trimer complexes revealed a horizontal binding angle to the Env spike. These vaccine-elicited mAbs target the V2 cap, demonstrating a means to accomplish tier 2 virus neutralization by penetrating the dense N-glycan shield., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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