Early antiretroviral therapy shapes the immunometabolic landscape without reducing the intact HIV reservoir

Objectives: We assessed the effect of early ART during acute HIV infection on reservoir dynamics, cytokine profile, and T-cell metabolism. Methods: We studied a longitudinal cohort of PWH starting ART during early (ET) or chronic (CT) infection, and a cross-sectional cohort including matched ET and CT participants (≥36 months virologically suppressed) and HIV-negative controls. We analysed total HIV-DNA, intact and defective proviruses, cell-associated HIV-RNA, plasma cytokines, and metabolomic profiles of CD4+ and CD8+T-cells. Results: Over 75% of ET participants started ART in Fiebig stages IV-VI. Early ART was associated with lower total HIV-DNA and cell-associated RNA. Although intact proviruses were similar between groups, they represented a larger proportion of the reservoir in ET participants. Worse pre-ART immune status correlated with a larger and more transcriptionally active reservoir. Regulatory, inflammatory, and homeostatic cytokines negatively correlated with the intact reservoir, particularly in CT participants. Metabolomic profiling of T-cells demonstrated ART timing-dependent alterations in several metabolic pathways. Metabolites involved in glycolysis, amino-acid metabolism, and polyol pathways positively correlated with HIV transcription in CD4⁺T-cells, especially in CT participants. Conclusion: Early ART limits the HIV reservoir size, shapes its composition, and influences immunometabolic pathways, though it might not be enough to reduce the intact reservoir.