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Natural killer (NK) cells possess inherent antiviral activity, but unmodified NK cells have limited ability to recognize or clear latently infected cells during ART suppression. We engineered allogeneic human primary NK cells expressing a truncated CD4-based chimeric antigen receptor (D1D2-CAR) that targets the conserved CD4 binding site on HIV Env without permitting viral entry, and evaluated their activities in humanized mice infected with barcoded CCR5-tropic HIV. D1D2-CAR NK cells selectively killed HIV-infected primary CD4 T cells in vitro and significantly delayed viral rebound following ART interruption in humanized mice compared to GFP-NK or no NK control groups. Barcoded HIV tracking showed that CAR-NK treatment reduced the number, diversity, and inter-organ overlap of rebounding viral RNA and proviral DNA lineages, yielding rebound driven by a restricted set of dominant clones. Integration site and chromatin analysis further demonstrated selective depletion of proviruses positioned in genes, enhancers, promoters, and open chromatin. These findings show that CAR-NK cells can target rare reactivation events during ART suppression and reshape the reservoir toward a less rebound-competent, epigenetically repressive state.<\/jats:p>","DOI":"10.64898\/2026.01.22.700964","type":"posted-content","created":{"date-parts":[[2026,1,25]],"date-time":"2026-01-25T05:10:13Z","timestamp":1769317813000},"source":"Crossref","is-referenced-by-count":1,"title":["NK Cells Engineered with a Chimeric Antigen Receptor Delay HIV Rebound and Reshape HIV Reservoir Composition"],"prefix":"10.64898","author":[{"given":"Yuan","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6649-2461","authenticated-orcid":false,"given":"Izra","family":"Abbaali","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, University of California Los Angeles, Los Angeles, California, 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Harvey","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, University of California Los Angeles, Los Angeles, California, 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Kostelny","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongying","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, University of California Los Angeles, Los Angeles, California, 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Dimapasoc","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4821-1400","authenticated-orcid":false,"given":"Christopher","family":"Seet","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology and Oncology, University of California Los Angeles, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6946-7627","authenticated-orcid":false,"given":"Catherine A.","family":"Blish","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5486-8495","authenticated-orcid":false,"given":"Jerome A.","family":"Zack","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, California, USA"},{"name":"Department of Medicine, Division of Hematology and Oncology, University of California Los Angeles, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7040-5773","authenticated-orcid":false,"given":"Jocelyn T.","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, University of California Los Angeles, Los Angeles, California, 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026020503440877000_2026.01.22.700964v1.1","unstructured":"HIV. https:\/\/www.who.int\/data\/gho\/data\/themes\/hiv-aids."},{"key":"2026020503440877000_2026.01.22.700964v1.2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI9006"},{"key":"2026020503440877000_2026.01.22.700964v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-0898-8"},{"key":"2026020503440877000_2026.01.22.700964v1.4","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1097\/COH.0000000000000954","article-title":"The power of ten in HIV remission: insights from hematopoietic stem cell transplantation","volume":"20","year":"2025","journal-title":"Curr. 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