Elucidating the mechanism underlying incomplete immune recovery in people living with HIV through CD4⁺ and CD8⁺ T cell multi-omics

Abstract

A subset of people living with HIV (PLHIV), known as immunological non-responders (INR), fails to achieve adequate CD4⁺ T cell recovery despite viral suppression with antiretroviral therapy (ART). These individuals face an increased risk of adverse clinical outcomes. This study aims to explore the intracellular mechanisms and molecular signatures underlying this incomplete immune recovery using a multi-omics approach. The study analysed CD4⁺ and CD8⁺ T cells from 100 ART-naïve PLHIV. Participants were classified into controls (baseline CD4⁺ > 200 cells/µL, n = 49) and cases (baseline CD4⁺ ≤ 200 cells/µL, n = 51). Cases were further categorised after 48 weeks of ART as immunological responders (IR, n = 34) or INR ( n = 16) based on a recovery cut-off of 250 cells/µL. The research employed integrative proteomic and metabolomic analyses, adjusted for sex, complemented by miRNA and qRT-PCR validation in a subset of samples to identify differential molecular signatures. In CD4⁺ T cells, a baseline signature of 381 proteins and 45 metabolites significantly differentiated controls from cases; notably, 34 proteins and 16 metabolites specifically discriminated future IR from INR before starting treatment. CD8⁺ T cells showed a more limited signature with minimal stratification between IR and INR. Integrative analysis revealed coordinated dysregulation in CD4⁺ T cells of INR, characterised by altered glycolytic flux, metabolic exhaustion, and oxidative stress. Exploratory analyses via miRNA and qRT-PCR confirmed these findings and suggested post-transcriptional mechanisms contribute to the impairment. Incomplete immune recovery in PLHIV is primarily driven by pre-existing metabolic dysfunction and oxidative stress within CD4⁺ T cells, rather than CD8⁺ T cells. These findings identify specific molecular signatures present before ART initiation, highlighting early potential therapeutic targets and strategies to enhance immune reconstitution in this vulnerable population.