Daily HIV pre-exposure prophylaxis enhances monocyte activation and reprogrammes immune cell metabolism.

INTRODUCTION: Pre-exposure prophylaxis (PrEP) with tenofovir/emtricitabine (TDF/FTC) is highly effective for HIV prevention. While antiretroviral therapy (ART) is linked to chronic inflammation in people living with HIV, its direct effects on immune phenotype, function, and metabolism in HIV-negative individuals remain unclear. This study aimed to investigate how daily TDF/FTC pre-exposure prophylaxis modulates immune activation, functional responses, and metabolic programming in innate and adaptive immune cells in HIV-negative individuals. METHODS: Gay, bisexual, and other men who have sex with men (gbMSM) on daily TDF/FTC PrEP underwent immunophenotyping and single-cell metabolic profiling using SCENITH™. Cytokine and chemokine responses were measured ex vivo and after lipopolysaccharide or Mycobacterium tuberculosis stimulation. Responses were compared with those of a demographically similar PrEP-naïve cohort, and five participants were followed longitudinally for 6-9 months after PrEP initiation. RESULTS: Monocytes from people taking PrEP (n=15; median 533 days) exhibited higher activation marker expression (HLA-DR, CD14) ex vivo and enhanced IL-1β and TNF after bacterial challenge compared with PrEP-naïve individuals (n=11). Longitudinal follow-up of a pilot cohort (n=5) suggested that PrEP initiation increased monocyte activation marker expression (HLA-DR, CD14, CD40, TNFRI/II) and cytokine production (IL-1β, TNF, GM-CSF, IFN-γ, Granzyme B, MIP-1α). Reduced glucose dependency was observed in monocytes, CD56dim NK cells and CD4+ T cells 6-9 months after PrEP initiation. DISCUSSION: Daily TDF/FTC promotes monocyte activation, enhances pro-inflammatory responses, and appears to reprogramme immune cell metabolism, highlighting ART's potential to modulate immune-mediated inflammatory pathways in HIV-negative individuals.