{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:08:43Z","timestamp":1790705323471,"version":"4.1.0"},"reference-count":82,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,26]],"date-time":"2023-01-26T00:00:00Z","timestamp":1674691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006348","name":"Delaney AIDS Research Enterprise","doi-asserted-by":"publisher","award":["1UM1AI126611-01 , 1UM 1AI164560-01"],"award-info":[{"award-number":["1UM1AI126611-01 , 1UM 1AI164560-01"]}],"id":[{"id":"10.13039\/100006348","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1149990"],"award-info":[{"award-number":["APP1149990"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>HIV-1 persists in resting CD4<jats:sup>+<\/jats:sup> T-cells despite antiretroviral therapy (ART). Determining the cell surface markers that enrich for genetically-intact HIV-1 genomes is vital in developing targeted curative strategies. Previous studies have found that HIV-1 proviral DNA is enriched in CD4<jats:sup>+<\/jats:sup> T-cells expressing the immune checkpoint markers programmed cell death protein-1 (PD-1) or cytotoxic T-lymphocyte associated protein-4 (CTLA-4). There has also been some success in blocking these markers in an effort to reverse HIV-1 latency. However, it remains unclear whether cells expressing PD-1 and\/or CTLA-4 are enriched for genetically-intact, and potentially replication-competent, HIV-1 genomes. <\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We obtained peripheral blood from 16 HIV-1-infected participants, and paired lymph node from four of these participants, during effective ART. Memory CD4<jats:sup>+<\/jats:sup> T-cells from either site were sorted into four populations: PD-1<jats:sup>-<\/jats:sup>CTLA-4<jats:sup>-<\/jats:sup> (double negative, DN), PD-1<jats:sup>+<\/jats:sup>CTLA-4<jats:sup>-<\/jats:sup> (PD-1<jats:sup>+<\/jats:sup>), PD-1<jats:sup>-<\/jats:sup>CTLA-4<jats:sup>+<\/jats:sup> (CTLA-4<jats:sup>+<\/jats:sup>) and PD-1<jats:sup>+<\/jats:sup>CTLA-4<jats:sup>+<\/jats:sup> (double positive, DP). We performed an exploratory study using the full-length individual proviral sequencing (FLIPS) assay to identify genetically-intact and defective genomes from each subset, as well as HIV-1 genomes with specific intact open reading frames (ORFs). <\/jats:p><\/jats:sec><jats:sec><jats:title>Results and Discussion<\/jats:title><jats:p>In peripheral blood, we observed that proviruses found within PD-1<jats:sup>+<\/jats:sup> cells are more likely to have intact ORFs for genes such as <jats:italic>tat<\/jats:italic>, <jats:italic>rev<\/jats:italic> and <jats:italic>nef<\/jats:italic> compared to DN, CTLA-4<jats:sup>+<\/jats:sup> and DP cells, all of which may contribute to HIV-1 persistence. Conversely, we observed that CTLA-4 expression is a marker for cells harbouring HIV-1 provirus that is more likely to be defective, containing low levels of these intact ORFs. In the lymph node, we found evidence that CTLA-4<jats:sup>+<\/jats:sup> cells contain lower levels of HIV-1 provirus compared to the other cell subsets. Importantly, however, we observed significant participant variation in the enrichment of HIV-1 proviruses with intact genomes or specific intact ORFs across these memory CD4<jats:sup>+<\/jats:sup> T-cell subsets, and therefore consideration of additional cellular markers will likely be needed to consistently identify cells harbouring latent, and potentially replication-competent, HIV-1. <\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1064346","type":"journal-article","created":{"date-parts":[[2023,1,26]],"date-time":"2023-01-26T11:43:39Z","timestamp":1674733419000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Unequal distribution of genetically-intact HIV-1 proviruses in cells expressing the immune checkpoint markers PD-1 and\/or CTLA-4"],"prefix":"10.3389","volume":"14","author":[{"given":"Katie","family":"Fisher","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy E.","family":"Schlub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoe","family":"Boyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas A.","family":"Rasmussen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajantha","family":"Rhodes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Hoh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick M.","family":"Hecht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven 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