{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T09:43:45Z","timestamp":1792230225764,"version":"4.4.0"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T00:00:00Z","timestamp":1757289600000},"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><jats:title>Background<\/jats:title><jats:p>People living with chronic HIV (PLWH) show immune dysfunction, despite viral suppression and normal CD4 recovery, particularly those with low CD4\/CD8 ratios. Subjacent cellular alterations of such a reliable marker of clinical progression remain elusive.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Categorization by CD4\/CD8 ratio after three year of therapy (R &amp;lt; 0.8\/R &amp;gt; 1.2, <jats:italic>n<\/jats:italic> = 28\/<jats:italic>n<\/jats:italic> = 24) and <jats:italic>post-hoc<\/jats:italic> reclassification by nadir-CD4 (<jats:italic>N<\/jats:italic> \u2264 350\/<jats:italic>N<\/jats:italic> &amp;gt; 350) were performed in PLWH achieving viral suppression and CD4 \u2265 500. CD4 T cell\u2013associated viral reservoir, as well as metabolism-related gene expression, glucose uptake ability, relative telomere length (RTL), and thymic output for CD4 and CD8 T cells, were determined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Patients with a CD4\/CD8 ratio &amp;lt; 0.8 exhibited reduced CD8 T-cell glucose uptake ability after stimulation (<jats:italic>p<\/jats:italic> = 0.007) and trends to shorter RTL (<jats:italic>p<\/jats:italic> = 0.093) and to larger CD4-associated viral reservoir (<jats:italic>p<\/jats:italic> = 0.068) than <jats:italic>R<\/jats:italic> &amp;gt; 1.2. Differently, patients with nadir \u2264350 exhibited altered CD4 and CD8 T-cell expression of metabolism-related genes, although no differences in glucose uptake ability, and shorter RTL in both cell subsets, but similar viral reservoir to patients with nadir &amp;gt;350. Remarkably, viral reservoir and both CD4 and CD8 thymic output showed inverse associations (<jats:italic>r<\/jats:italic> = \u22120.623, <jats:italic>p<\/jats:italic> = 0.01 and <jats:italic>r<\/jats:italic> = \u22120.661, <jats:italic>p<\/jats:italic>\u00a0= 0.038, respectively).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>A low CD4\/CD8 ratio in chronic PLWH stands on a larger viral reservoir in CD4 T cells and metabolic alterations in CD8 T cells, probably related to its exhaustion and compromised effector functionality, and thymic output could contribute to such alterations. Patients with lower nadir-CD4 showed a resting-like CD4 phenotype and a metabolically active CD8 subset, without further viral reservoir extension. Persistence of low CD4\/CD8 ratio and low nadir-CD4 counts seems to rely on different immune damage.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1617674","type":"journal-article","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T04:12:44Z","timestamp":1757304764000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Unveiling altered CD8 T-cell metabolism and homeostatic proliferation behind a low CD4\/CD8 ratio in ART-suppressed HIV individuals with normal CD4 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