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.