Garrido Rodríguez, VanesaBulnes Ramos, ÁngelOlivas Martínez, IsraelMar Pozo Balado, María delTejerina-Picado, FranciscoGutiérrez, FélixMarco Sánchez, CristinaTiraboschi, Juan ManuelCastillo Navarro, AntoniaBernal, EnriqueGarcía Guerrero, María C.Puertas Castro, Ma. CarmenPeraire, JoaquimRull, AnnaMartínez Picado, Francisco JavierPacheco, Yolanda MaríaCoRIS cohort2025-10-152025-10-152025-09-081664‑3224https://hdl.handle.net/2445/223661Background: 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. Methods: Categorization by CD4/CD8 ratio after three year of therapy (R < 0.8/R > 1.2, n = 28/n = 24) and post-hoc reclassification by nadir-CD4 (N <= 350/N > 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. Results: Patients with a CD4/CD8 ratio < 0.8 exhibited reduced CD8 T-cell glucose uptake ability after stimulation (p = 0.007) and trends to shorter RTL (p = 0.093) and to larger CD4-associated viral reservoir (p = 0.068) than R > 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 (r = -0.623, p = 0.01 and r = -0.661, p = 0.038, respectively). Conclusion: 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.11 p.application/pdfengcc-by (c) Garrido Rodríguez, Vanesa et al., 2025http://creativecommons.org/licenses/by/3.0/es/Cèl·lules TImmunopatologiaVIH (Virus)T cellsImmunopathologyHIV (Viruses)info:eu-repo/semantics/article2025-10-14info:eu-repo/semantics/openAccess40990014