{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T04:31:00Z","timestamp":1786681860922,"version":"build-2736575974"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010414","name":"Health Research Board","doi-asserted-by":"publisher","award":["EIA-2019-010, ILP-POR-2022-033, ILP-2024-044"],"award-info":[{"award-number":["EIA-2019-010, ILP-POR-2022-033, ILP-2024-044"]}],"id":[{"id":"10.13039\/100010414","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Pre-exposure prophylaxis (PrEP) with tenofovir\/emtricitabine (TDF\/FTC) is highly effective for HIV prevention. While antiretroviral therapy (ART) is linked to chronic inflammation in people living with HIV, its direct effects on immune phenotype, function, and metabolism in HIV-negative individuals remain unclear. This study aimed to investigate how daily TDF\/FTC pre-exposure prophylaxis modulates immune activation, functional responses, and metabolic programming in innate and adaptive immune cells in HIV-negative individuals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Gay, bisexual, and other men who have sex with men (gbMSM) on daily TDF\/FTC PrEP underwent immunophenotyping and single-cell metabolic profiling using SCENITH\u2122. Cytokine and chemokine responses were measured ex vivo and after lipopolysaccharide or\n                      <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                      stimulation. Responses were compared with those of a demographically similar PrEP-na\u00efve cohort, and five participants were followed longitudinally for 6\u20139 months after PrEP initiation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Monocytes from people taking PrEP (n=15; median 533 days) exhibited higher activation marker expression (HLA-DR, CD14)\n                      <jats:italic>ex vivo<\/jats:italic>\n                      and enhanced IL-1\u03b2 and TNF after bacterial challenge compared with PrEP-na\u00efve individuals (n=11). Longitudinal follow-up of a pilot cohort (n=5) suggested that PrEP initiation increased monocyte activation marker expression (HLA-DR, CD14, CD40, TNFRI\/II) and cytokine production (IL-1\u03b2, TNF, GM-CSF, IFN-\u03b3, Granzyme B, MIP-1\u03b1). Reduced glucose dependency was observed in monocytes, CD56\n                      <jats:sup>dim<\/jats:sup>\n                      NK cells and CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells 6\u20139 months after PrEP initiation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Daily TDF\/FTC promotes monocyte activation, enhances pro-inflammatory responses, and appears to reprogramme immune cell metabolism, highlighting ART\u2019s potential to modulate immune-mediated inflammatory pathways in HIV-negative individuals.<\/jats:p>\n                  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