| Title: |
Potency and durability of T and B cell immune responses after homologous and heterologous vector delivery of a trimer-stabilized, membrane-displayed HIV-1 clade ConC Env protein. |
| Authors: |
Perdiguero, B.; Hauser, A.; Gómez, C.E.; Peterhoff, D.; Sideris, E.; Sorzano, CÓS; Wilmschen, S.; Schaber, M.; Stengel, L.; Asbach, B.; Ding, S.; Von Laer, D.; Levy, Y.; Pantaleo, G.; Kimpel, J.; Esteban, M.; Wagner, R. |
| Publication Year: |
2023 |
| Collection: |
Université de Lausanne (UNIL): Serval - Serveur académique lausannois |
| Subject Terms: |
Animals; Mice; HIV Antibodies; HIV-1/genetics; Membrane Proteins; env Gene Products; Human Immunodeficiency Virus/genetics; Antibodies; Neutralizing; HIV Seropositivity; AIDS Vaccines/genetics; Immunity; DNA; HIV-1 vaccine; T and B cells; VSV-GP and NYVAC vectors; membrane display; mice immunization; trimeric ConCv5 KIKO protein |
| Description: |
The generation of an HIV-1 vaccine able to induce long-lasting protective immunity remains a main challenge. Here, we aimed to modify next-generation soluble, prefusion-stabilized, close-to-native, glycan-engineered clade C gp140 envelope (Env) trimers (sC23v4 KIKO and ConCv5 KIKO) for optimal display on the cell surface following homologous or heterologous vector delivery. A combination of the following modifications scored best regarding the preservation of closed, native-like Env trimer conformation and antigenicity when using a panel of selected broadly neutralizing (bnAb) and non-neutralizing (nnAb) monoclonal antibodies for flow cytometry: i) replacing the natural cleavage site with a native flexible linker and introducing a single amino acid substitution to prevent CD4 binding (*), ii) fusing a heterologous VSV-G-derived transmembrane moiety to the gp140 C-terminus, and iii) deleting six residues proximal to the membrane. When delivering membrane-tethered sC23v4 KIKO* and ConCv5 KIKO* via DNA, VSV-GP, and NYVAC vectors, the two native-like Env trimers provide differential antigenicity profiles. Whereas such patterns were largely consistent among the different vectors for either Env trimer, the membrane-tethered ConCv5 KIKO* trimer adopted a more closed and native-like structure than sC23v4 KIKO*. In immunized mice, VSV-GP and NYVAC vectors expressing the membrane-tethered ConCv5 KIKO* administered in prime/boost combination were the most effective regimens for the priming of Env-specific CD4 T cells among all tested combinations. The subsequent booster administration of trimeric ConCv5 KIKO* Env protein preserved the T cell activation levels between groups. The evaluation of the HIV-1-specific humoral responses induced in the different immunization groups after protein boosts showed that the various prime/boost protocols elicited broad and potent antibody responses, preferentially of a Th1-associated IgG2a subclass, and that the obtained antibody levels remained high at the memory phase. In summary, we ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| ISSN: |
1664-3224 |
| Relation: |
Frontiers in Immunology; https://iris.unil.ch/handle/iris/198873; serval:BIB_D789F3FAEA8A; 001112406600001 |
| DOI: |
10.3389/fimmu.2023.1270908 |
| Availability: |
https://iris.unil.ch/handle/iris/198873; https://doi.org/10.3389/fimmu.2023.1270908 |
| Accession Number: |
edsbas.13D93A0B |
| Database: |
BASE |