title: Intra-spike crosslinking overcomes antibody evasion by HIV-1.
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.
authors: Division of Biology and Biological Engineering, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA.
authors: Rachel P
authors: RP
authors: Galimidi
authors: Division of Biology and Biological Engineering, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA.
authors: Joshua S
authors: JS
authors: Klein
authors: Division of Biology and Biological Engineering, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA.
authors: Maria S
authors: MS
authors: Politzer
authors: Division of Biology and Biological Engineering, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA.
authors: Shiyu
authors: S
authors: Bai
authors: Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors: Michael S
authors: MS
authors: Seaman
authors: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute.
authors: Michel C
authors: MC
authors: Nussenzweig
authors: Division of Biology and Biological Engineering, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA.
authors: Anthony P
authors: AP
authors: West
authors: 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.
authors: Pamela J
authors: PJ
authors: Bjorkman
mesh_terms: D057134:Antibodies, Neutralizing / Q000737:chemistry* / Q000276:immunology; D003432:Cross-Linking Reagents / Q000378:metabolism; D018360:Crystallography, X-Ray; D000939:Epitopes; D015483:HIV Antibodies / Q000737:chemistry* / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015497:HIV-1; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry*; D007074:Immunoglobulin G / Q000737:chemistry* / Q000276:immunology; D015202:Protein Engineering
chemical_list: D057134:Antibodies, Neutralizing; D003432:Cross-Linking Reagents; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; C514793:gp120 protein, Human immunodeficiency virus 1
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