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Cell. 2015 Jan 29;160(3):433-46. doi: 10.1016/j.cell.2015.01.016.

Intra-spike crosslinking overcomes antibody evasion by HIV-1.

Author information

1
Division of Biology and Biological Engineering, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA.
2
Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
3
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute.
4
Division of Biology and Biological Engineering, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA; Howard Hughes Medical Institute. Electronic address: bjorkman@caltech.edu.

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.

PMID:
25635457
PMCID:
PMC4401576
DOI:
10.1016/j.cell.2015.01.016
[Indexed for MEDLINE]
Free PMC Article
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