{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T01:54:32Z","timestamp":1773366872333,"version":"3.50.1"},"posted":{"date-parts":[[2025,12,15]]},"group-title":"Immunology","reference-count":102,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIH","award":["R01-AI176597"],"award-info":[{"award-number":["R01-AI176597"]}]},{"name":"NIH","award":["P30-AI045008"],"award-info":[{"award-number":["P30-AI045008"]}]},{"name":"NIH","award":["UM-1AI164570"],"award-info":[{"award-number":["UM-1AI164570"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The multifaceted and long-lived nature of HIV-1 reservoirs has proven to be a formidable obstacle in the development of a therapeutic cure of HIV-1. One of the major dimensions of the HIV-1 reservoir is its prevalence and persistence in tissue environments, including in lymph nodes (LN). Within LN, T follicular helper (Tfh) cells are widely considered as the dominant sub-reservoir in viremic people with HIV (PWH). However, whether Tfh cells survive to establish a reservoir in PWH undergoing suppressive antiretroviral therapy (ART) has remained controversial. To address these issues, we deeply phenotyped over 500,000 cells and identified over 2,000 HIV-1 infected cells by employing single-cell multiomics on LN from PWH during viremia and suppressed on ART. While we detected HIV-1 infected Tfh cells, the majority of infected cells during viremia and ART had non-follicular phenotypes and were instead heterogeneously distributed between various CD4+ T-cell subsets. Within-subset comparisons of HIV+ and HIV- cells revealed heightened activation signatures and altered cell cycle states during viremia, but largely similar features during ART. Furthermore, the comparison between viremia and ART in PWH highlighted a noncanonical Tfh subset - defined by high locus accessibility and transcription of\n                  <jats:italic>PRDM1<\/jats:italic>\n                  - that is selectively depleted during viremia, recovers after ART, and is highly susceptible to infection in vitro. Our work suggests a revised direction for the HIV-1 cure field where a mandate of any comprehensive strategy will be to address the high proportional burden of non-follicular cells within the HIV reservoir.\n                <\/jats:p>","DOI":"10.64898\/2025.12.11.693731","type":"posted-content","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T17:05:11Z","timestamp":1765818311000},"source":"Crossref","is-referenced-by-count":1,"title":["Selective infection and loss of PRDM1+ LN Tfh cells in uncontrolled HIV infection precludes formation of Tfh reservoirs under ART"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8640-6065","authenticated-orcid":false,"given":"Vincent H.","family":"Wu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jayme M.L.","family":"Nordin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. 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