Intra-spike crosslinking overcomes antibody evasion by HIV-1.
Cell
; 160(3): 433-46, 2015 Jan 29.
Article
em En
| MEDLINE
| ID: mdl-25635457
ABSTRACT
Antibodies developed during HIV-1 infection lose efficacy as the viral spike mutates. We postulated that anti-HIV-1 antibodies primarily bind monovalently because HIV's low spike density impedes bivalent binding through inter-spike crosslinking, and the spike structure prohibits bivalent binding through intra-spike crosslinking. Monovalent binding reduces avidity and potency, thus expanding the range of mutations permitting antibody evasion. To test this idea, we engineered antibody-based molecules capable of bivalent binding through intra-spike crosslinking. We used DNA as a "molecular ruler" to measure intra-epitope distances on virion-bound spikes and construct intra-spike crosslinking molecules. Optimal bivalent reagents exhibited up to 2.5 orders of magnitude increased potency (>100-fold average increases across virus panels) and identified conformational states of virion-bound spikes. The demonstration that intra-spike crosslinking lowers the concentration of antibodies required for neutralization supports the hypothesis that low spike densities facilitate antibody evasion and the use of molecules capable of intra-spike crosslinking for therapy or passive protection.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Imunoglobulina G
/
Fragmentos Fab das Imunoglobulinas
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Anticorpos Anti-HIV
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HIV-1
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Anticorpos Neutralizantes
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article