Immunofocusing and enhancing autologous Tier-2 HIV-1 neutralization by displaying Env trimers on two-component protein nanoparticles

Brouwer, P. J. M.; Antanasijevic, A.; de Gast, M.; Allen, J. D.; Bijl, T. P. L.; Yasmeen, A.; Ravichandran, R.; Burger, J.; Ozorowski, G.; Torres, J. L.; LaBranche, C.; Montefiori, D.; Ringe, R. P.; van Gils, M.; Moore, J. P.; Klasse, P. J.; Crispin, M.; King, N. P.; Ward, A.; Sanders, R. W.

doi:10.1101/2020.11.30.403543

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bioRxiv · 10.1101/2020.11.30.403543

Immunofocusing and enhancing autologous Tier-2 HIV-1 neutralization by displaying Env trimers on two-component protein nanoparticles

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Abstract

The HIV-1 envelope glycoprotein trimer is poorly immunogenic because it is covered by a dense glycan shield. As a result, recombinant Env glycoproteins generally elicit inadequate antibody levels that neutralize clinically-relevant, neutralization-resistant (Tier-2) HIV-1 strains. Multivalent antigen presentation on nanoparticles is an established strategy to increase vaccine-driven immune responses. However, due to nanoparticle instability in vivo, the display of non-native Env structures, and the inaccessibility of many neutralizing antibody (NAb) epitopes, the effects of nanoparticle display have been modest for Env trimers. Here, we generated two-component self-assembling protein nanoparticles presenting twenty SOSIP trimers of the clade C Tier-2 genotype 16055. An immunization study in rabbits demonstrated that these nanoparticles induced 60-fold higher autologous Tier-2 NAb titers than the corresponding SOSIP trimers. Epitope mapping revealed that nanoparticle presentation focused antibody responses to an immunodominant apical epitope. Thus, these nanoparticles are a promising platform to improve the immunogenicity of Env trimers with apex-proximate NAb epitopes.

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Brouwer, P. J. M., Antanasijevic, A., de Gast, M., Allen, J. D., Bijl, T. P. L., Yasmeen, A., Ravichandran, R., Burger, J., Ozorowski, G., Torres, J. L., LaBranche, C., Montefiori, D., Ringe, R. P., van Gils, M., Moore, J. P., Klasse, P. J., Crispin, M., King, N. P., Ward, A., Sanders, R. W.. 2020-11-30. Immunofocusing and enhancing autologous Tier-2 HIV-1 neutralization by displaying Env trimers on two-component protein nanoparticles. https://doi.org/10.1101/2020.11.30.403543

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