Carbohydrate-functionalized nanovaccines preserve HIV-1 antigen stability and activate antigen presenting cells

Abstract

The functionalization of polymeric nanoparticles with ligands that target specific receptors on immune cells offers the opportunity to tailor adjuvant properties by conferring pathogen mimicking attributes to the particles. Polyanhydride nanoparticles are promising vaccine adjuvants with desirable characteristics such as immunomodulation, sustained antigen release, activation of antigen presenting cells (APCs), and stabilization of protein antigens. These capabilities can be exploited to design nanovaccines against viral pathogens, such as HIV-1, due to the important role of dendritic cells (DCs) and macrophages in viral spread. In this work, an optimized process was developed for carbohydrate functionalization of HIV-1 antigen-loaded polyanhydride nanoparticles. The carbohydrate-functionalized nanoparticles preserved antigenic properties upon release and also enabled sustained antigen release kinetics. Particle internalization was observed to be chemistry-dependent with positively charged nanoparticles being taken up more efficiently by DCs. Up-regulation of the activation makers CD40 and CD206 was demonstrated with carboxymethyl-α-d-mannopyranosyl-(1,2)-d-mannopyranoside functionalized nanoparticles. The secretion of the cytokines IL-6 and TNF-α was shown to be chemistry-dependent upon stimulation with carbohydrate-functionalized nanoparticles. These results offer important new insights upon the interactions between carbohydrate-functionalized nanoparticles and APCs and provide foundational information for the rational design of targeted nanovaccines against HIV-1.

Keywords:

• dendritic cells
• carbohydrates
• nanoparticles
• polyanhydrides
• targeting
• HIV antigen
• nanovaccines

Acknowledgments

The authors acknowledge financial support from NIH-NIAID (U19 AI-091031). The authors acknowledge useful discussions with Dr Michael J. Wannemuehler on the DC activation data and thank Shawn Rigby of the Iowa State University Flow Cytometry facility for his assistance with the flow cytometry experiments. MWC has an equity interest in NeoVaxSyn Incorporated, and serves as CEO/President. NeoVaxSyn Inc. did not contribute to this work or to the interpretation of the data. The following reagents were obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: HIV-1 gp41 mAb 2F5, 4E10, and Z13e1.