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

Autor: Robert Parks, Yaroslav Tsybovsky, Kevin O. Saunders, Ramiro A. Ramirez-Valdez, Barbara J. Flynn, Constantinos Petrovas, Barton F. Haynes, Geoffrey M. Lynn, William E. Walkowicz, Guillaume Stewart-Jones, Gabriela Mužíková, Kartika Padhan, Joseph R. Francica, Ladislav Androvič, Robert A. Seder, Richard Laga, Stephen D. Schmidt, Faezzah Baharom, Baptiste Aussedat
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Immunogen
B Cells
Physiology
HIV Infections
HIV Envelope Protein gp120
Biochemistry
Immune Receptors
Epitope
White Blood Cells
Epitopes
Mice
0302 clinical medicine
Animal Cells
Immune Physiology
HIV Seropositivity
Medicine and Health Sciences
Nanotechnology
Biology (General)
Enzyme-Linked Immunoassays
Toll-like Receptors
Immune Response
AIDS Vaccines
Vaccines
Mice
Inbred BALB C
Immune System Proteins
General Neuroscience
Immunogenicity
Antibody titer
Infectious Diseases
Engineering and Technology
Female
Cellular Types
General Agricultural and Biological Sciences
Research Article
Signal Transduction
Primates
Glycan
Infectious Disease Control
medicine.drug_class
QH301-705.5
Immune Cells
Immunology
Antigen-Presenting Cells
Biology
Monoclonal antibody
Research and Analysis Methods
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
Antigen
medicine
Animals
Antigens
Antibody-Producing Cells
Immunoassays
Blood Cells
General Immunology and Microbiology
Biology and Life Sciences
Proteins
HIV envelope protein
Cell Biology
Virology
Antibodies
Neutralizing
Macaca mulatta
030104 developmental biology
Antibody Formation
biology.protein
Immunologic Techniques
HIV-1
Nanoparticles
Peptides
030217 neurology & neurosurgery
Zdroj: PLoS Biology
PLoS Biology, Vol 17, Iss 6, p e3000328 (2019)
ISSN: 1545-7885
1544-9173
Popis: 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 biocompatible N-[(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 broadly neutralizing antibodies (bnAbs). When administered with a potent Toll-like receptor (TLR) 7/8 agonist adjuvant, these nanoparticles elicited high antibody binding titers to the V3 site. Similar to human V3/glycan bnAbs, certain monoclonal antibodies (mAbs) elicited by this vaccine were glycan dependent or targeted the GDIR peptide motif. To improve affinity to native Env trimer affinity, nonhuman primates (NHPs) were boosted with various SOSIP Env proteins; however, significant neutralization was not observed. Taken together, this study provides a new vaccine platform for administration of glycopeptide immunogens for focusing immune responses to specific bnAb epitopes.
Synthetic polymer-based nanoparticles effectively deliver HIV Env glycopeptide immunogens to lymph nodes and stimulate B cell lineages with characteristics resembling broadly neutralizing antibodies, in nonhuman primates.
Databáze: OpenAIRE
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