Peterhoff, David and Thalhauser, Stefanie and Neckermann, Patrick and Barbey, Clara and Straub, Kristina and Nazet, Julian and Merkl, Rainer and Laengst, Gernot and Breunig, Miriam and Wagner, Ralf (2022) Multivalent display of engineered HIV-1 envelope trimers on silica nanoparticles for targeting and in vitro activation of germline VRC01 B cells. EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, 181. pp. 88-101. ISSN 0939-6411, 1873-3441
Full text not available from this repository. (Request a copy)Abstract
Selective targeting of germline B cells with specifically designed germline-targeting HIV-1 envelope immunogens (GT-Env) is considered a feasible vaccination strategy to elicit broadly neutralizing antibodies (bnAbs). BnAbs are extremely valuable because they neutralize genetically distant viral strains at the same time. To overcome its inherently low affinity to germline B cells, the aim of the study was to present GT-Env via different immobili-zation strategies densely arrayed on the surface of nanoparticles. We engineered a prefusion-stabilized GT-Env trimer with affinity to VRC01 germline B cells using a bioinformatics-supported design approach. Distinct glycan modifications and amino acid substitutions yielded a GT-Env trimer which bound to the receptor with a KD of 11.5 mu M. Silica nanoparticles with 200 nm diameter (SiNPs) were used for the multivalent display of the novel GT-Env with a 15 nm mean centre-to-centre spacing either by site-specific, covalent conjugation or at random, non-specific adsorption. Oriented, covalent GT-Env conjugation revealed better binding of structure dependent bnAbs as compared to non-specifically adsorbed GT-Env. In addition, GT-Env covalently attached activated a B cell line expressing the germline VRC01 receptor at an EC50 value in the nanomolar range (4 nM), while soluble GT-Env required 1,000-fold higher concentrations to induce signalling. The significantly lower GT-Env con-centration was likely required due to avidity effects, which were in the picomolar range. Thus, low affinity antigens may particularly benefit from a particulate and multivalent delivery. In future, SiNPs are ideal to be modified in a modular design with various GT-Env variants that target different stages of germline and bnAb precursor B cells.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | BROADLY NEUTRALIZING ANTIBODIES; ANTI-HIV-1 ANTIBODIES; RESPONSES; VACCINE; RECEPTORS; PROTEIN; DESIGN; STABILIZATION; IMMUNIZATION; DOMAIN; Nanotechnology; Silica nanoparticles; HIV-1; Vaccine; Immunogen design; Germline-targeting; Env; B cells; Multivalent interaction; Affinity; Avidity |
| Subjects: | 600 Technology > 610 Medical sciences Medicine 600 Technology > 615 Pharmacy |
| Divisions: | Medicine > Lehrstuhl für Medizinische Mikrobiologie und Hygiene Biology, Preclinical Medicine > Institut für Biochemie, Genetik und Mikrobiologie > Lehrstuhl für Biochemie III > Prof. Dr. Gernot Längst Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical Technology (Prof. Göpferich) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 26 Jan 2024 05:52 |
| Last Modified: | 26 Jan 2024 05:52 |
| URI: | https://pred.uni-regensburg.de/id/eprint/56501 |
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