{"doi":"10.1371/journal.ppat.1009404","title":"Robust CAR-T memory formation and function via hematopoietic stem cell delivery","abstract":"Due to the durability and persistence of reservoirs of HIV-1-infected cells, combination antiretroviral therapy (ART) is insufficient in eradicating infection. Achieving HIV-1 cure or sustained remission without ART treatment will require the enhanced and persistent effective antiviral immune responses. Chimeric Antigen Receptor (CAR) T-cells have emerged as a powerful immunotherapy and show promise in treating HIV-1 infection. Persistence, trafficking, and maintenance of function remain to be a challenge in many of these approaches, which are based on peripheral T cell modification. To overcome many of these issues, we have previously demonstrated successful long-term engraftment and production of anti-HIV CAR T cells in modified hematopoietic stem cells (HSCs) in vivo. Here we report the development and in vivo testing of second generation CD4-based CARs (CD4CAR) against HIV-1 infection using a HSCs-based approach. We found that a modified, truncated CD4-based CAR (D1D2CAR) allows better CAR-T cell differentiation from gene modified HSCs, and maintains similar CTL activity as compared to the full length CD4-based CAR. In addition, D1D2CAR does not mediate HIV infection or stimulation mediated by IL-16, suggesting lower risk of off-target effects. Interestingly, stimulatory domains of 4-1BB but not CD28 allowed successful hematopoietic differentiation and improved anti-viral function of CAR T cells from CAR modified HSCs. Addition of 4-1BB to CD4 based CARs led to faster suppression of viremia during early untreated HIV-1 infection. D1D2CAR 4-1BB mice had faster viral suppression in combination with ART and better persistence of CAR T cells during ART. In summary, our data indicate that the D1D2CAR-41BB is a superior CAR, showing better HSC differentiation, viral suppression and persistence, and less deleterious functions compared to the original CD4CAR, and should continue to be pursued as a candidate for clinical study.","journal":"PLoS Pathogens","year":2021,"id":164529,"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":38,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9534,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":350444,"name":"Mayra A. Carrillo","orcid":"0000-0003-3430-1226","position":1,"is_corresponding":false},{"id":350443,"name":"Wenli Mu","orcid":"0000-0003-2244-510X","position":2,"is_corresponding":false},{"id":414524,"name":"Valerie Rezek","orcid":"0000-0002-2336-7599","position":3,"is_corresponding":false},{"id":686443,"name":"Heather Martin","orcid":"0000-0003-2791-0293","position":4,"is_corresponding":false},{"id":414525,"name":"Philip Hamid","orcid":"0000-0003-1146-7397","position":5,"is_corresponding":false},{"id":499074,"name":"Irvin S. Y. Chen","orcid":"0000-0003-1199-2415","position":6,"is_corresponding":false},{"id":377122,"name":"Otto O. Yang","orcid":"0000-0003-1970-8992","position":7,"is_corresponding":false},{"id":344324,"name":"Jerome A. Zack","orcid":"0000-0001-5486-8495","position":8,"is_corresponding":false},{"id":263554,"name":"Scott G. Kitchen","orcid":"0000-0001-6182-6082","position":9,"is_corresponding":false},{"id":680592,"name":"Anjie Zhen","orcid":"0000-0001-6139-7820","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-18T23:45:32.226038Z","pmid":"33793675","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":[]}