{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T13:19:35Z","timestamp":1792070375265,"version":"4.4.0"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T00:00:00Z","timestamp":1770595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Despite successful antiretroviral therapy (ART) that restores CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell counts and reduces HIV viral loads to undetectable levels, a substantial proportion of people living with HIV (PLWH) exhibit persistent CD4\/CD8 ratio inversion. This abnormal ratio is primarily driven by sustained CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell expansion and reflects a state of chronic immune dysregulation and incomplete immune recovery. However, cellular and molecular mechanisms underlying this discordant immune state remain poorly understood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed longitudinal data of 5,416 ART-treated PLWH from Shenzhen Third People\u2019s Hospital, identifying distinct CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell trajectory groups using group-based trajectory modeling. We compared those with chronic stable activation (CSA group) versus those with immune modulation recovery (IMR group) using CyTOF-based immunophenotyping, bulk RNA sequencing, and plasma biomarker profiling.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Both IMR and CSA groups achieved CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell recovery, but CSA group exhibited persistently elevated CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells and inverted CD4\/CD8 ratios. The CSA group displayed a marked expansion of senescent and activated CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell subsets and diminished regulatory T cells, characterized by decreased expression of CD196, CD95, and CD27. Bulk RNA sequencing revealed upregulation of interferon-stimulated genes, chemokine signaling pathways and pro-inflammatory transcriptional programs. Consistently, systemic levels of key inflammatory mediators, including IP-10, MCP-1, and soluble CD163, were significantly elevated in the CSA group.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Persistent CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell activation reflects a distinct immunological state marked by CD4\/CD8 ratio inversion, cell senescence, exhaustion, and systemic inflammation. This immune profile may help identify individuals who warrant closer immunological monitoring for non-AIDS complications and may inform future studies aimed at modulating CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell-driven immune dysregulation to improve long-term immune restoration.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1735779","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T05:22:15Z","timestamp":1770614535000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Persistent CD8+ T cell-driven immune dysregulation despite normalized CD4+ T cell recovery in ART-treated people living with HIV"],"prefix":"10.3389","volume":"17","author":[{"given":"Yiyao","family":"Hu","sequence":"first","affiliation":[{"name":"School of Public Health, Shenzhen University Medical School","place":["Shenzhen, 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