Daily HIV pre-exposure prophylaxis enhances monocyte activation and effector function and reprogrammes cellular metabolism.

BackgroundPre-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. MethodsGay, 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. These were compared with a demographically similar PrEP-naive cohort, with five individuals followed 6-9 months after PrEP initiation. FindingsMonocytes from people taking PrEP (n=15; median 533 days) exhibited higher activation marker expression (HLA-DR, CD14) ex vivo and enhanced IL-1{beta} and TNF after bacterial challenge compared with PrEP-naive individuals (n=11). Longitudinal follow-up indicated that PrEP initiation increased monocyte activation markers (HLA-DR, CD14, CD40, TNFRI/II) and cytokine production (IL-1{beta}, TNF, GM-CSF, IFN-{gamma}, Granzyme B, MIP-1). Reduced glucose dependency was observed in monocytes, CD56dim NK cells and CD4+ T cells 6-9 months after PrEP initiation. InterpretationDaily TDF/FTC promotes monocyte activation, enhances pro-inflammatory responses, and reprogrammes immune cell metabolism, highlighting ARTs potential to modulate immune-mediated inflammatory pathways in HIV-negative individuals. FundingTrinity Translational Medicine Institute, Trinity College Dublin, Dublin, The Association of Physicians of Great Britain and Ireland, Health Research Board Ireland. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/698427v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@d48088org.highwire.dtl.DTLVardef@1428926org.highwire.dtl.DTLVardef@13a4facorg.highwire.dtl.DTLVardef@144d1f1_HPS_FORMAT_FIGEXP M_FIG C_FIG Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSDespite effective viral suppression with antiretroviral therapy (ART), people living with HIV (PLWHIV) experience persistent immune activation and chronic inflammation that increase their risk of age-associated comorbidities. The extent to which ART itself contributes to this dysregulated immune state remains unclear, as HIV infection confounds most studies. Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) offers a unique opportunity to examine the direct immunological effects of ART in HIV-negative individuals. However, few studies have explored how PrEP influences immune cell activation, effector function, or cellular metabolism in the absence of viral infection. Added value of this studyThis study is the first to characterise how daily PrEP with TDF/FTC modulates innate immune activation and cellular metabolism independently of HIV infection. We show that PrEP enhances monocyte activation and effector cytokine production while reprogramming metabolic pathways to reduce glucose dependency in monocytes, NK cells, and CD4 T cells. These findings reveal previously unrecognised immunometabolic effects of ART in HIV-negative individuals, providing mechanistic insight into how ART exposure can shape immune homeostasis in the absence of infection. Implications of all the available evidenceOur findings, together with existing data from PLWHIV, suggest that ART itself can remodel immune and metabolic pathways, potentially contributing to both beneficial and detrimental outcomes. ART-induced immunometabolic reprogramming may underlie persistent inflammation and the early onset of comorbidities observed in treated HIV infection, while also enhancing innate responsiveness to bacterial pathogens such as Mycobacterium tuberculosis. Understanding these mechanisms may inform future strategies to optimise ART regimens and mitigate inflammation-associated complications.