{"doi":"10.1101/2024.11.13.623476","title":"Anti-HIV-1 HSPC-based gene therapy with safety kill switch to defend against and attack HIV-1 infection","abstract":"Hematopoietic stem/progenitor cell (HSPC)-based anti-HIV-1 gene therapy holds promise to provide life-long remission following a single treatment. Here we report a multi-pronged anti-HIV-1 HSPC-based gene therapy designed to defend against and attack HIV-1 infection. We developed a lentiviral vector capable of co-expressing three anti-HIV-1 genes. Two are designed to prevent infection, including a short-hairpin RNA (CCR5sh1005) to knock down HIV-1 co-receptor CCR5 and a membrane anchored HIV-1 fusion inhibitor (C46). The third gene is a CD4-based chimeric antigen receptor (CAR) designed to attack HIV-1 infected cells. Our vector also includes a non-signaling truncated human epidermal growth factor receptor (huEGFRt) which acts as a negative selection-based safety kill switch against transduced cells. Anti-HIV-1 vector-transduced human CD34+ HSPC efficiently reconstituted multi-lineage human hematopoietic cells in humanized bone marrow/liver/thymus (huBLT) mice. HIV-1 viral load was significantly reduced (1-log fold reduction, p <0.001) in transplanted huBLT mice. Anti-huEGFR monoclonal antibody Cetuximab (CTX) administration significantly reduced huEGFRt+ vector-modified cells (>4-fold reduction, p <0.01) in huBLT mice. These results demonstrate that our strategy is highly effective for HIV-1 inhibition, and that CTX-mediated negative selection can deplete anti-HIV-1 vector-modified cells in the event of unwanted adverse effects in huBLT mice.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":506091,"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":0.9512,"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":857303,"name":"Keval Parikh","orcid":"0000-0002-8661-5924","position":1,"is_corresponding":false},{"id":1131962,"name":"Jian Zhang","orcid":"0009-0007-1262-4805","position":2,"is_corresponding":false},{"id":1132361,"name":"Alexander Brinkley","orcid":null,"position":3,"is_corresponding":false},{"id":402592,"name":"Grace Chen","orcid":"0000-0001-9236-3180","position":4,"is_corresponding":false},{"id":1357393,"name":"Natnicha Jakramonpreeya","orcid":null,"position":5,"is_corresponding":false},{"id":680592,"name":"Anjie Zhen","orcid":"0000-0001-6139-7820","position":6,"is_corresponding":false},{"id":585617,"name":"Dong Sung An","orcid":"0000-0002-7020-9470","position":7,"is_corresponding":false},{"id":1357088,"name":"Qi Guo","orcid":"0000-0003-3145-1309","position":0,"is_corresponding":true}],"reference_count":78,"raw_metadata":null,"created_at":"2026-07-19T02:10:50.984927Z","pmid":"39605384","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":[]}