Structure-Based Stabilization of HIV-1 gp120 Enhances Humoral Immune Responses to the Induced Co-Receptor Binding Site

PLoS Pathogens

Gerald Voss¹  George Shaw²  Ling Xu³  Peter D. Kwong³  Barna Dey³  Tongqing Zhou³  John R. Mascola³  Krisha Svehla³  Gary J. Nabel³  Adhuna Phogat³  Richard T. Wyatt³  Yuxing Li³  Bimal K. Chakrabarti³  Dianne Wycuff³ 

[1] GlaxoSmithKline Biologicals, Rixensart, Belgium;University of Alabama Birmingham, Birmingham, Alabama, United States of America;Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America

关键词: Antibodies;    Enzyme-linked immunoassays;    Antigens;    HIV-1;    Immune serum;    Entropy;    HIV-2;    Coreceptors;   

DOI  :  10.1371/journal.ppat.1000445

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The human immunodeficiency virus type 1 (HIV-1) exterior envelope glycoprotein, gp120, possesses conserved binding sites for interaction with the primary virus receptor, CD4, and also for the co-receptor, generally CCR5. Although gp120 is a major target for virus-specific neutralizing antibodies, the gp120 variable elements and its malleable nature contribute to evasion of effective host-neutralizing antibodies. To understand the conformational character and immunogenicity of the gp120 receptor binding sites as potential vaccine targets, we introduced structure-based modifications to stabilize gp120 core proteins (deleted of the gp120 major variable regions) into the conformation recognized by both receptors. Thermodynamic analysis of the re-engineered core with selected ligands revealed significant stabilization of the receptor-binding regions. Stabilization of the co-receptor-binding region was associated with a marked increase in on-rate of ligand binding to this site as determined by surface plasmon resonance. Rabbit immunization studies showed that the conformational stabilization of core proteins, along with increased ligand affinity, was associated with strikingly enhanced humoral immune responses against the co-receptor-binding site. These results demonstrate that structure-based approaches can be exploited to stabilize a conformational site in a large functional protein to enhance immunogenic responses specific for that region.

【 授权许可】

CC BY