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Immunity. 2017 May 16;46(5):804-817.e7. doi: 10.1016/j.immuni.2017.04.021.

Particulate Array of Well-Ordered HIV Clade C Env Trimers Elicits Neutralizing Antibodies that Display a Unique V2 Cap Approach.

Author information

1
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
2
IAVI Neutralizing Antibody Center, Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
3
Immunology and Allergy Unit, Department of Medicine, Karolinska Institutet, 171 77 Solna, Sweden.
4
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
5
Astrid Fagraeus Laboratory, Comparative Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
6
IAVI Neutralizing Antibody Center, Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: wyatt@scripps.edu.
7
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Electronic address: gunilla.karlsson.hedestam@ki.se.

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.

KEYWORDS:

B cell responses; HIV-1; clade C; envelope glycoproteins; epitope; germinal centers; liposome; monoclonal antibody; trimers; vaccine

PMID:
28514687
PMCID:
PMC5528178
DOI:
10.1016/j.immuni.2017.04.021
[Indexed for MEDLINE]
Free PMC Article

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