Star nanoparticles delivering HIV-1 peptide minimal immunogens elicit near-native envelope antibody responses in nonhuman primates

by Joseph R. Francica, Richard Laga, Geoffrey M. Lynn, Gabriela Mu žíková, Ladislav Androvič, Baptiste Aussedat, William E. Walkowicz, Kartika Padhan, Ramiro Andrei Ramirez-Valdez, Robert Parks, Stephen D. Schmidt, Barbara J. Flynn, Yaroslav Tsybovsky, Guillaume B. E. Stewart-Jones, Kevin O. Saunders, Faezzah Baharom, Constantinos Petrovas, Barton F. Haynes, Ro bert A. Seder Peptide immunogens provide an approach to focus antibody responses to specific neutralizing sites on the HIV envelope protein (Env) trimer or on other pathogens. However, the physical characteristics of peptide immunogens can limit their pharmacokinetic and immunological properties. Here, we have designed synthetic “star” nanoparticles based on biocompatibleN-[(2-hydroxypropyl)methacrylamide] (HPMA)-based polymer arms extending from a poly(amidoamine) (PAMAM) dendrimer core. In mice, these star nanoparticles trafficked to lymph nodes (LNs) by 4 hours following vaccination, where they were taken up by subcapsular macrophages and then resident dendritic cells (DCs). Immunogenicity optimization studies revealed a correlation of immunogen density with antibody titers. Furthermore, the co-delivery of Env variable loop 3 (V3) and T-helper peptides induced titers that were 2 logs higher than if the peptides were given in separate nanoparticles. Finally, we performed a nonhuman primate (NHP) study using a V3 glycopeptide minimal immunogen that was structurally optimized to be recognized by Env V3/glycan ...
Source: PLoS Biology: Archived Table of Contents - Category: Biology Authors: Source Type: research