Perdiguero, Beatriz and Hauser, Alexandra and Gomez, Carmen Elena and Peterhoff, David and Sideris, Eleftheria and Sorzano, Carlos Oscar S. and Wilmschen, Sarah and Schaber, Marion and Stengel, Laura and Asbach, Benedikt and Ding, Song and Von Laer, Dorothee and Levy, Yves and Pantaleo, Giuseppe and Kimpel, Janine and Esteban, Mariano and Wagner, Ralf (2023) 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. FRONTIERS IN IMMUNOLOGY, 14: 1270908. ISSN 1664-3224,
Full text not available from this repository. (Request a copy)Abstract
IntroductionThe 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.MethodsA 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.ResultsWhen 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.DiscussionIn summary, we provide a feasible strategy to display multiple copies of native-like Env trimers on the cell surface, which translates into efficient priming of sustained CD4+ T cell responses after vector delivery as well as broad, potent, and sustained antibody responses following booster immunizations with the homologous, prefusion-stabilized, close-to-native ConCv5 KIKO* gp140 Env trimer.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | BROADLY NEUTRALIZING ANTIBODIES; ENVELOPE GLYCOPROTEIN COMPLEX; VESICULAR STOMATITIS-VIRUS; DNA PRIME; DEPENDENT EPITOPE; RHESUS MACAQUES; TFH CELLS; IMMUNOGENICITY; ACTIVATION; PROTECTION; trimeric ConCv5 KIKO protein; HIV-1 vaccine; DNA; VSV-GP and NYVAC vectors; membrane display; mice immunization; T and B cells; antibodies |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Medizinische Mikrobiologie und Hygiene |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 13 Mar 2024 13:10 |
| Last Modified: | 13 Mar 2024 13:10 |
| URI: | https://pred.uni-regensburg.de/id/eprint/59937 |
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