biostudies-literatureUnknown16Garrido-Rodriguez V<h4>Background</h4>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.<h4>Methods</h4>Categorization by CD4/CD8 ratio after three year of therapy (R < 0.8/R > 1.2, <i>n</i> = 28/<i>n</i> = 24) and <i>post-hoc</i> reclassification by nadir-CD4 (<i>N</i> ≤ 350/<i>N</i> > 350) were performed in PLWH achieving viral suppression and CD4 ≥ 500. CD4 T cell-associated 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.<h4>Results</h4>Patients with a CD4/CD8 ratio < 0.8 exhibited reduced CD8 T-cell glucose uptake ability after stimulation (<i>p</i> = 0.007) and trends to shorter RTL (<i>p</i> = 0.093) and to larger CD4-associated viral reservoir (<i>p</i> = 0.068) than <i>R</i> > 1.2. Differently, patients with nadir ≤350 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 >350. Remarkably, viral reservoir and both CD4 and CD8 thymic output showed inverse associations (<i>r</i> = -0.623, <i>p</i> = 0.01 and <i>r</i> = -0.661, <i>p</i> = 0.038, respectively).<h4>Conclusion</h4>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.Frontiers in immunology1617674https://www.ebi.ac.uk/biostudies/studies/S-EPMC12450686biostudies-literatureUnveiling altered CD8 T-cell metabolism and homeostatic proliferation behind a low CD4/CD8 ratio in ART-suppressed HIV individuals with normal CD4 recovery.PMC12450686Tiraboschi JMPeraire JPozo-Balado MDMMartinez-Picado JTejerina-Picado FPacheco YMCastillo-Navarro ABernal EGutierrez FRull ABulnes-Ramos AMarco-Sanchez COlivas-Martinez IGarcia-Guerrero MCPuertas MCGarrido-Rodriguez VfalseUnveiling altered CD8 T-cell metabolism and homeostatic proliferation behind a low CD4/CD8 ratio in ART-suppressed HIV individuals with normal CD4 recovery.<h4>Background</h4>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.<h4>Methods</h4>Categorization by CD4/CD8 ratio after three year of therapy (R < 0.8/R > 1.2, <i>n</i> = 28/<i>n</i> = 24) and <i>post-hoc</i> reclassification by nadir-CD4 (<i>N</i> ≤ 350/<i>N</i> > 350) were performed in PLWH achieving viral suppression and CD4 ≥ 500. CD4 T cell-associated 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.<h4>Results</h4>Patients with a CD4/CD8 ratio < 0.8 exhibited reduced CD8 T-cell glucose uptake ability after stimulation (<i>p</i> = 0.007) and trends to shorter RTL (<i>p</i> = 0.093) and to larger CD4-associated viral reservoir (<i>p</i> = 0.068) than <i>R</i> > 1.2. Differently, patients with nadir ≤350 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 >350. Remarkably, viral reservoir and both CD4 and CD8 thymic output showed inverse associations (<i>r</i> = -0.623, <i>p</i> = 0.01 and <i>r</i> = -0.661, <i>p</i> = 0.038, respectively).<h4>Conclusion</h4>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.2025-01-01T00:00:00Z20252026-06-03T19:17:58.022Z2026-05-30T03:06:31.852ZS-EPMC124506864099001410.3389/fimmu.2025.1617674