Research Grants Program Office (RGPO)
Intra-spike crosslinking overcomes antibody evasion by HIV-1.
- Author(s): Galimidi, Rachel P
- Klein, Joshua S
- Politzer, Maria S
- Bai, Shiyu
- Seaman, Michael S
- Nussenzweig, Michel C
- West, Anthony P
- Bjorkman, Pamela J
- et al.
Published Web Locationhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401576/
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.