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In this study, we address some requirements of CAR motifs for strong surface expression of a novel anti-HIV CAR by evaluating important elements in the extracellular, hinge, and transmembrane (TM) domains. When combining a truncated CD4 extracellular domain and CD8\u03b1 hinge\/TM, the novel CAR did not express extracellularly but was detectable intracellularly. By shortening the CD8\u03b1 hinge, CD4-CAR surface expression was partially recovered and addition of the LYC motif at the end of the CD8\u03b1 TM fully recovered both intracellular and extracellular CAR expression. Mutation of LYC to TTA or TTC showed severe abrogation of CAR expression by flow cytometry and confocal microscopy. Additionally, we determined that CD4-CAR surface expression could be maximized by the removal of FQKAS motif at the junction of the extracellular domain and the hinge region. CD4-CAR surface expression also resulted in cytotoxic CAR T cell killing of HIV Env<jats:sup>+<\/jats:sup> target cells. In this study, we identified elements that are crucial for optimal CAR surface expression, highlighting the need for structural analysis studies to establish fundamental guidelines of CAR designs.<\/jats:p>","DOI":"10.1371\/journal.pone.0293990","type":"journal-article","created":{"date-parts":[[2024,8,12]],"date-time":"2024-08-12T17:23:36Z","timestamp":1723483416000},"page":"e0293990","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Extracellular domain, hinge, and transmembrane determinants affecting surface CD4 expression of a novel anti-HIV chimeric antigen receptor (CAR) construct"],"prefix":"10.1371","volume":"19","author":[{"given":"Giorgio","family":"Zenere","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengxiang","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecily C.","family":"Midkiff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan M.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher P.","family":"Grice","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2967-5186","authenticated-orcid":true,"given":"William C.","family":"Wimley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amitinder","family":"Kaur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4521-2678","authenticated-orcid":true,"given":"Stephen E.","family":"Braun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,8,12]]},"reference":[{"issue":"18","key":"pone.0293990.ref001","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.126345","article-title":"ROR1-CAR T cells are effective against lung and breast cancer in advanced microphysiologic 3D tumor models","volume":"4","author":"L. 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