|Title||Intra-Spike Crosslinking Overcomes Antibody Evasion by HIV-1.|
|Publication Type||Journal Article|
|Year of Publication||2015|
|Authors||Galimidi RP, Klein JS, Politzer MS, Bai S, Seaman MS, Nussenzweig MC, West AP, Bjorkman PJ|
|Date Published||2015 Jan 29|
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.
|Grant List||DP1 OD006961 / OD / NIH HHS / United States |
P01 AI100148 / AI / NIAID NIH HHS / United States
Intra-Spike Crosslinking Overcomes Antibody Evasion by HIV-1.