{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T20:51:05Z","timestamp":1783025465680,"version":"3.54.6"},"reference-count":44,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T00:00:00Z","timestamp":1771977600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T00:00:00Z","timestamp":1771977600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Medical Virology"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The current highly active antiretroviral therapy (HAART or ART) effectively suppresses de novo HIV\u20101 infection but fails to eliminate HIV reservoir cells, which leads to rapid viral rebound upon ART cessation. Chimeric antigen receptor (CAR) T cells engineered to target HIV\u20101 Env\u207a cells offer a promising strategy to eliminate or control these persistent reservoirs and achieve durable control of HIV\u20101 infection. However, a major challenge is the susceptibility of such CAR\u2010T cells to HIV infection, especially those soluble CD4 (sCD4)\u2010based CAR\u2010T cells. In this study, an sCD4\u2010based CAR incorporating the S85C mutation in the CD4 Ig\u2010like domain 1 (termed D1C) was engineered to enable disulfide bond formation with the HIV\u20101 envelope glycoprotein (Env), thereby reducing viral entry and conferring protection against HIV infection. D1C\/sCD4 CAR\u2010T cells exhibited enhanced T\u2010cell activation and cytotoxicity in response to Env stimulation while demonstrating resistance HIV\u20101 infection in vitro and in vivo. Furthermore, the herpesvirus entry mediator (HVEM) intracellular domain was identified as an optimal costimulatory domain, enhancing cytokine induction, cytotoxicity, and promoting a favorable central memory phenotype and persistence of CAR\u2010T cells. In humanized mouse models, D1C\/sCD4 CAR\u2010T cells demonstrated superior persistence and improved control of HIV rebound following ART interruption compared to wild\u2010type (WT)\/sCD4 CAR\u2010T cells. These findings highlight a novel strategy to enhance the efficacy and durability of HIV\u2010targeted CAR\u2010T cell therapy by combining HIV resistance and optimized co\u2010stimulation.<\/jats:p>","DOI":"10.1002\/jmv.70853","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T14:24:39Z","timestamp":1772979879000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["CD4\u2010Based Chimeric Antigen Receptor (CAR)\u2010T Cells With Resistance to HIV\u20101 Infection and Enhanced Anti\u2010HIV Efficacy: Covalent Interaction Between CD4\u2010CAR and HIV\u20101 Envelope Glycoprotein"],"prefix":"10.1002","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4915-867X","authenticated-orcid":false,"given":"Yaoxian","family":"Lou","sequence":"first","affiliation":[{"name":"Department of Microbiologyand Immunology, Institute of Human Virology University of MarylandSchool of Medicine Baltimore Maryland USA"},{"name":"Department of Pharmacology&amp; 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Physiology, Institute of HumanVirology, Marlene and Stewart Greenebaum Comprehensive Cancer Center University of MarylandSchool of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianping","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Microbiologyand Immunology, Lineberger ComprehensiveCancer Center The University of NorthCarolina at Chapel Hill Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwei","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Microbiologyand Immunology, Lineberger ComprehensiveCancer Center The University of NorthCarolina at Chapel Hill Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Institute of Human Virology University of Maryland School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianpietro","family":"Dotti","sequence":"additional","affiliation":[{"name":"Department of Microbiologyand Immunology, Lineberger ComprehensiveCancer Center The University of NorthCarolina at Chapel Hill Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7798-3605","authenticated-orcid":false,"given":"Mohammad","family":"Sajadi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Institute of Human Virology University of Maryland School of Medicine Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lishan","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Microbiologyand Immunology, Institute of Human Virology University of MarylandSchool of Medicine Baltimore Maryland USA"},{"name":"Department of Pharmacology&amp; 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