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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<jats:italic>in vivo<\/jats:italic>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.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009404","type":"journal-article","created":{"date-parts":[[2021,4,1]],"date-time":"2021-04-01T17:54:27Z","timestamp":1617299667000},"page":"e1009404","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":31,"title":["Robust CAR-T memory formation and function via hematopoietic stem cell delivery"],"prefix":"10.1371","volume":"17","author":[{"given":"Anjie","family":"Zhen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3430-1226","authenticated-orcid":true,"given":"Mayra A.","family":"Carrillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenli","family":"Mu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Rezek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2791-0293","authenticated-orcid":true,"given":"Heather","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1146-7397","authenticated-orcid":true,"given":"Philip","family":"Hamid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1199-2415","authenticated-orcid":true,"given":"Irvin S. Y.","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1970-8992","authenticated-orcid":true,"given":"Otto O.","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5486-8495","authenticated-orcid":true,"given":"Jerome A.","family":"Zack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6182-6082","authenticated-orcid":true,"given":"Scott G.","family":"Kitchen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,4,1]]},"reference":[{"key":"ppat.1009404.ref001","doi-asserted-by":"crossref","first-page":"a007096","DOI":"10.1101\/cshperspect.a007096","article-title":"HIV latency","volume":"1","author":"R. F. 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Cruikshank","year":"2000","journal-title":"Journal of leukocyte biology"},{"key":"ppat.1009404.ref035","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.4049\/jimmunol.162.3.1431","article-title":"Profound enhancement of T cell activation mediated by the interaction between the TCR and the D3 domain of CD4","volume":"162","author":"D. A. Vignali","year":"1999","journal-title":"Journal of immunology (Baltimore, Md.: 1950)"},{"key":"ppat.1009404.ref036","doi-asserted-by":"crossref","first-page":"401","DOI":"10.2217\/imt-2016-0121","article-title":"Chimeric antigen receptor engineered stem cells: a novel HIV therapy","volume":"9","author":"A. Zhen","year":"2017","journal-title":"Immunotherapy"},{"key":"ppat.1009404.ref037","doi-asserted-by":"crossref","first-page":"e1049","DOI":"10.1002\/cti2.1049","article-title":"Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations","volume":"8","author":"R. 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Chmielewski","year":"2014","journal-title":"Immunological reviews"},{"key":"ppat.1009404.ref046","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.96976","article-title":"Enhancing CAR T cell persistence through ICOS and 4-1BB costimulation","volume":"3","author":"S. Guedan","year":"2018","journal-title":"JCI insight"},{"key":"ppat.1009404.ref047","doi-asserted-by":"crossref","first-page":"E564","DOI":"10.1073\/pnas.1717765115","article-title":"Fitness landscape of the human immunodeficiency virus envelope protein that is targeted by antibodies","volume":"115","author":"R. H. Y. Louie","year":"2018","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"ppat.1009404.ref048","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.chom.2017.12.004","article-title":"Getting the \"Kill\" into \"Shock and Kill\": Strategies to Eliminate Latent HIV","volume":"23","author":"Y. Kim","year":"2018","journal-title":"Cell Host Microbe"},{"key":"ppat.1009404.ref049","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1016\/j.ymthe.2019.03.008","article-title":"Lentiviral Vector-Based Dendritic Cell Vaccine Suppresses HIV Replication in Humanized Mice","volume":"27","author":"T. D. 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