{"doi":"10.3389/fimmu.2023.1270908","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","abstract":"Introduction: 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. Methods: 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. Results: 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. Discussion: 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.","journal":"Frontiers in Immunology","year":2023,"id":377999,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9531,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1141935,"name":"Alexandra Hauser","orcid":"0000-0002-9738-392X","position":1,"is_corresponding":false},{"id":14363,"name":"Carmen Gómez","orcid":"0000-0002-5414-7935","position":2,"is_corresponding":false},{"id":1141936,"name":"David Peterhoff","orcid":"0000-0001-5911-6233","position":3,"is_corresponding":false},{"id":1142403,"name":"Elefthéria Sideris","orcid":null,"position":4,"is_corresponding":false},{"id":327200,"name":"Carlos Óscar S. Sorzano","orcid":"0000-0002-9473-283X","position":5,"is_corresponding":false},{"id":1142404,"name":"Sarah Wilmschen","orcid":null,"position":6,"is_corresponding":false},{"id":1142405,"name":"Marion Schaber","orcid":null,"position":7,"is_corresponding":false},{"id":1141937,"name":"Laura Stengel","orcid":"0009-0004-8940-3515","position":8,"is_corresponding":false},{"id":938310,"name":"Benedikt Asbach","orcid":"0000-0003-1056-8591","position":9,"is_corresponding":false},{"id":475186,"name":"S.-W Ding","orcid":"0000-0001-8069-1056","position":10,"is_corresponding":false},{"id":576171,"name":"Dorotheé von Laer","orcid":"0000-0001-5825-7237","position":11,"is_corresponding":false},{"id":724111,"name":"Yves Lévy","orcid":"0000-0002-5549-6256","position":12,"is_corresponding":false},{"id":41012,"name":"Giuseppe Pantaleo","orcid":"0000-0003-3651-2721","position":13,"is_corresponding":false},{"id":851452,"name":"Janine Kimpel","orcid":"0000-0002-5210-7905","position":14,"is_corresponding":false},{"id":974080,"name":"Mariano Estéban","orcid":"0000-0003-0846-2827","position":15,"is_corresponding":false},{"id":420014,"name":"Ralf Wagner","orcid":"0000-0002-2029-3846","position":16,"is_corresponding":false},{"id":974079,"name":"Beatriz Perdiguero","orcid":"0000-0001-6276-7766","position":0,"is_corresponding":true}],"reference_count":94,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:16:44.708019Z","pmid":"38045703","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}