{"doi":"10.17615/7ajk-yx28","title":"Ex vivo and in vivo suppression of SARS-CoV-2 with combinatorial AAV/RNAi expression vectors","abstract":"Despite rapid development and deployment of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), clinically relevant modalities to curb the pandemic by directly attacking the virus on a genetic level remain highly desirable and are urgently needed. Here we comprehensively illustrate the capacity of adeno-associated virus (AAV) vectors co-expressing a cocktail of three short hairpin RNAs (shRNAs; RNAi triggers) directed against the SARS-CoV-2 RdRp and N genes as versatile and effective antiviral agents. In cultured monkey cells and human gut organoids, our most potent vector, SAVIOR (SARS virus repressor), suppressed SARS-CoV-2 infection to background levels. Strikingly, in control experiments using single shRNAs, multiple SARS-CoV-2 escape mutants quickly emerged from infected cells within 24–48 h. Importantly, such adverse viral adaptation was fully prevented with the triple-shRNA AAV vector even during long-term cultivation. In addition, AAV-SAVIOR efficiently purged SARS-CoV-2 in a new model of chronically infected human intestinal cells. Finally, intranasal AAV-SAVIOR delivery using an AAV9 capsid moderately diminished viral loads and/or alleviated disease symptoms in hACE2-transgenic or wild-type mice infected with human or mouse SARS-CoV-2 strains, respectively. Our combinatorial and customizable AAV/RNAi vector complements ongoing global efforts to control the coronavirus disease 2019 (COVID-19) pandemic and holds great potential for clinical translation as an original and flexible preventive or therapeutic antiviral measure.","journal":"UNC Libraries","year":2024,"id":499697,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9579,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":105602,"name":"Ande West","orcid":"0000-0001-7381-9533","position":1,"is_corresponding":false},{"id":237170,"name":"Steeve Boulant","orcid":"0000-0001-8614-4993","position":2,"is_corresponding":false},{"id":1193608,"name":"Leist S.R","orcid":null,"position":3,"is_corresponding":false},{"id":893249,"name":"Ali Ghanem","orcid":"0000-0003-4043-8958","position":4,"is_corresponding":false},{"id":20958,"name":"Katy Börner","orcid":"0000-0002-3321-6137","position":5,"is_corresponding":false},{"id":1185279,"name":"Tse L.V","orcid":null,"position":6,"is_corresponding":false},{"id":893677,"name":"Ina Ambiel","orcid":null,"position":7,"is_corresponding":false},{"id":68298,"name":"Dirk Grimm","orcid":"0000-0001-6227-5665","position":8,"is_corresponding":false},{"id":893247,"name":"Bettina Stolp","orcid":"0000-0003-2945-8536","position":9,"is_corresponding":false},{"id":893248,"name":"Olena Maiakovska","orcid":"0000-0002-3002-8712","position":10,"is_corresponding":false},{"id":736617,"name":"Ellen Wiedtke","orcid":null,"position":11,"is_corresponding":false},{"id":1348625,"name":"Fackler O.T","orcid":null,"position":12,"is_corresponding":false},{"id":1348626,"name":"Stanifer M.L","orcid":null,"position":13,"is_corresponding":false},{"id":893246,"name":"Jonas Becker","orcid":"0000-0003-3827-3322","position":14,"is_corresponding":false},{"id":1185287,"name":"Baric R.S","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:09:53.188165Z","pmid":null,"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":[]}