{"doi":"10.1016/j.omtm.2023.02.004","title":"A lentiviral vector B cell gene therapy platform for the delivery of the anti-HIV-1 eCD4-Ig-knob-in-hole-reversed immunoadhesin","abstract":"Barriers to effective gene therapy for many diseases include the number of modified target cells required to achieve therapeutic outcomes and host immune responses to expressed therapeutic proteins. As long-lived cells specialized for protein secretion, antibody-secreting B cells are an attractive target for foreign protein expression in blood and tissue. To neutralize HIV-1, we developed a lentiviral vector (LV) gene therapy platform for delivery of the anti-HIV-1 immunoadhesin, eCD4-Ig, to B cells. The EμB29 enhancer/promoter in the LV limited gene expression in non-B cell lineages. By engineering a knob-in-hole-reversed (KiHR) modification in the CH3-Fc eCD4-Ig domain, we reduced interactions between eCD4-Ig and endogenous B cell immunoglobulin G proteins, which improved HIV-1 neutralization potency. Unlike previous approaches in non-lymphoid cells, eCD4-Ig-KiHR produced in B cells promoted HIV-1 neutralizing protection without requiring exogenous TPST2, a tyrosine sulfation enzyme required for eCD4-Ig-KiHR function. This finding indicated that B cell machinery is well suited to produce therapeutic proteins. Lastly, to overcome the inefficient transduction efficiency associated with VSV-G LV delivery to primary B cells, an optimized measles pseudotyped LV packaging methodology achieved up to 75% transduction efficiency. Overall, our findings support the utility of B cell gene therapy platforms for therapeutic protein delivery.","journal":"Molecular Therapy — Methods & Clinical Development","year":2023,"id":342252,"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":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9507,"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":1078751,"name":"Stosh Ozog","orcid":"0000-0002-2120-9140","position":1,"is_corresponding":false},{"id":586644,"name":"Daniel P. Leaman","orcid":null,"position":2,"is_corresponding":false},{"id":861833,"name":"Rene Yu-Hong Cheng","orcid":"0000-0001-7946-100X","position":3,"is_corresponding":false},{"id":1078752,"name":"Nicholas J. Irons","orcid":"0000-0002-9720-8259","position":4,"is_corresponding":false},{"id":861835,"name":"Andee R. Ott","orcid":"0000-0002-3559-4166","position":5,"is_corresponding":false},{"id":457973,"name":"Claire M. Stoffers","orcid":null,"position":6,"is_corresponding":false},{"id":378922,"name":"Iram Khan","orcid":"0000-0003-4202-7108","position":7,"is_corresponding":false},{"id":1079247,"name":"Geraldine K.E. Goebrecht","orcid":null,"position":8,"is_corresponding":false},{"id":487296,"name":"Matthew R. Gardner","orcid":"0000-0003-2872-7597","position":9,"is_corresponding":false},{"id":104360,"name":"Michael Farzan","orcid":"0000-0002-2990-5319","position":10,"is_corresponding":false},{"id":108918,"name":"David J. Rawlings","orcid":"0000-0002-0810-1776","position":11,"is_corresponding":false},{"id":285907,"name":"Michael B. Zwick","orcid":"0000-0002-0885-2502","position":12,"is_corresponding":false},{"id":250992,"name":"Richard G. James","orcid":"0000-0002-2302-7367","position":13,"is_corresponding":false},{"id":296350,"name":"Bruce E. Torbett","orcid":"0000-0003-4995-1694","position":14,"is_corresponding":false},{"id":1078750,"name":"Eirini Vamva","orcid":"0000-0002-7896-4171","position":0,"is_corresponding":true}],"reference_count":100,"raw_metadata":null,"created_at":"2026-07-19T01:11:12.506815Z","pmid":"36879849","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":[]}