Upregulation of cellular exhaustion-related genes and CD4 + T cell disturbances in immunological non-responders on antiretroviral therapy

Abstract Antiretroviral therapy suppresses HIV replication, but 10–40% of people living with HIV do not reconstitute CD4 + T cell counts despite viral suppression. Cellular exhaustion and alteration in the frequency of CD4 + T cell subsets are mechanisms involved in immunological nonresponse. This study investigated cellular exhaustion through gene expression and frequencies of CD4 + T cell subpopulations through flow cytometry in 36 male individuals living with HIV (28 immunological responders and 8 immunological non-responders) after 18 months of treatment. Gene expression analysis revealed significantly upregulation of PDCD1 (fold change = 1.81; p = 0.0003) and TIGIT (fold change = 1.80; p = 0.0055) in immunological non-responders compared to immunological responders, with ROC curve analysis confirming discriminatory ability. Flow cytometry demonstrated lower frequencies of recent thymic emigrant (19.42 ± 7.76 vs. 32.29 ± 10.68; p = 0.0285) and naive CD4 + T cells (26.10 ± 9.41 vs. 47.65 ± 13.45; p = 0.0194) in immunological non-responders compared to immunological responders. Moreover, we observed higher frequency of central memory CD4 + T cells (47.94 ± 13.42 vs. 32.58 ± 9.89; p = 0.0184), with excellent discriminatory capacity. TIGIT expression inversely correlated with recent thymic emigrant ( r = -0.7284; p = 0.0013) and naive CD4 + T cells ( r = -0.7394; p = 0.0010), and directly with central memory CD4 + T cells ( r = 0.7264; p = 0.0014). These findings emphasize cellular exhaustion and dysregulated CD4 + T cell subsets as critical factors of immunological nonresponse.