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Here, we performed a comparative transcriptomic analysis of CD4\u207a T cells from HIV-infected individuals classified as elite controllers (EC), viremic controllers (VC), and chronic progressors (CP), aiming to identify IC signatures associated with viral control. ECs exhibited distinct expression profiles, characterized by significant upregulation of\n                    <jats:italic>CEACAM1<\/jats:italic>\n                    and\n                    <jats:italic>CD274<\/jats:italic>\n                    (\n                    <jats:italic>PD-L1<\/jats:italic>\n                    ), and downregulation of\n                    <jats:italic>CD200<\/jats:italic>\n                    ,\n                    <jats:italic>TIGIT<\/jats:italic>\n                    ,\n                    <jats:italic>CTLA4<\/jats:italic>\n                    ,\n                    <jats:italic>BTLA<\/jats:italic>\n                    , and\n                    <jats:italic>ADGRG1<\/jats:italic>\n                    relative to CPs. VC samples displayed intermediate expression levels. Principal component analysis (PCA) of IC genes revealed clear separation between ECs and CPs, driven largely by the differential expression of\n                    <jats:italic>PDCD1<\/jats:italic>\n                    ,\n                    <jats:italic>CTLA4<\/jats:italic>\n                    ,\n                    <jats:italic>TIGIT<\/jats:italic>\n                    , and\n                    <jats:italic>CD28<\/jats:italic>\n                    . ECs were also enriched in effector memory and Th2 CD4\u207a T cell subsets, which correlated positively with\n                    <jats:italic>CEACAM1<\/jats:italic>\n                    and\n                    <jats:italic>PD-L1<\/jats:italic>\n                    , and inversely with\n                    <jats:italic>TIGIT<\/jats:italic>\n                    and\n                    <jats:italic>CTLA4<\/jats:italic>\n                    . Co-expression network analysis identified two distinct gene modules: one (M2) containing\n                    <jats:italic>CEACAM1<\/jats:italic>\n                    and\n                    <jats:italic>PD-L1<\/jats:italic>\n                    , enriched for interferon signaling and NF-\u03baB pathways, and another (M4) comprising\n                    <jats:italic>TIGIT<\/jats:italic>\n                    ,\n                    <jats:italic>CD200<\/jats:italic>\n                    , and\n                    <jats:italic>BTLA<\/jats:italic>\n                    , enriched for TCR signaling and metabolic processes. Finally, comparison of ECs, ART-na\u00efve, and ART-treated individuals showed that pre-ART subjects displayed significantly elevated\n                    <jats:italic>ADGRG1<\/jats:italic>\n                    expression, which decreased following ART initiation, resembling the EC profile. These findings reveal checkpoint-related molecular signatures and cell subset compositions that stratify HIV-infected individuals by disease control phenotype, and highlight potential targets for immunomodulatory therapies aimed at achieving functional cure.\n                  <\/jats:p>","DOI":"10.1007\/s12026-026-09779-x","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T06:46:25Z","timestamp":1777445185000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immune checkpoint landscape in CD4\u207a T cells stratifies HIV-infected individuals by clinical progression"],"prefix":"10.1007","volume":"74","author":[{"given":"Serena","family":"Spampinato","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grazia","family":"Scuderi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelino","family":"Di Rosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Fagone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Nunnari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"key":"9779_CR1","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/S2055-6640(20)30275-2","volume":"5","author":"J Vanhamel","year":"2019","unstructured":"Vanhamel J, Bruggemans A, Debyser Z. 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