Intra-Spike Crosslinking Overcomes Antibody Evasion by HIV-1.

TitleIntra-Spike Crosslinking Overcomes Antibody Evasion by HIV-1.
Publication TypeJournal Article
Year of Publication2015
AuthorsGalimidi RP, Klein JS, Politzer MS, Bai S, Seaman MS, Nussenzweig MC, West AP, Bjorkman PJ
JournalCell
Volume160
Issue3
Pagination433-46
Date Published2015 Jan 29
ISSN1097-4172
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.

DOI10.1016/j.cell.2015.01.016
Alternate JournalCell
PubMed ID25635457
Grant ListDP1 OD006961 / OD / NIH HHS / United States
P01 AI100148 / AI / NIAID NIH HHS / United States
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