Daily HIV PrEP changes immune cells and metabolism, with TB implications

Antiretroviral drugs have transformed HIV care, but they may also change the immune system in ways we do not yet fully understand. Gráinne Jameson and colleagues set out to study that question by looking at people taking daily pre-exposure prophylaxis (PrEP) who do not have HIV. PrEP with tenofovir/emtricitabine (TDF/FTC) is widely used to prevent HIV infection, and it offers a rare chance to see the direct effects of antiretroviral drugs without the confounding influence of the virus itself. The research focused on gay, bisexual, and other men who have sex with men (gbMSM) using daily TDF/FTC PrEP and compared them with a demographically similar group not using PrEP. The team examined immune cell types and their behaviour, asking whether ART exposure alone changes immune activation, how cells respond to bacterial challenges, and whether cellular metabolism is altered. Because infections like tuberculosis are fought first by innate immune cells, the study also tested responses to Mycobacterium tuberculosis and to lipopolysaccharide, a bacterial stimulus, to see if PrEP changes how well the immune system reacts to such threats.

To investigate, the researchers used detailed immunophenotyping and single-cell metabolic profiling with SCENITH™. They measured cytokine and chemokine responses both directly from blood samples (ex vivo) and after stimulation with lipopolysaccharide or Mycobacterium tuberculosis. The study compared 15 people taking PrEP (median 533 days on TDF/FTC) with 11 PrEP-naïve individuals, and followed five participants longitudinally 6–9 months after starting PrEP. Key findings showed that monocytes from people on PrEP had higher expression of activation markers HLA-DR and CD14 and produced more IL-1β and TNF after bacterial challenge than monocytes from PrEP-naïve participants. In the five-person longitudinal group, PrEP initiation increased monocyte activation markers (HLA-DR, CD14, CD40, TNFRI/II) and raised production of IL-1β, TNF, GM-CSF, IFN-γ, Granzyme B, and MIP-1α. Metabolically, monocytes, CD56 dim NK cells and CD4 + T cells showed reduced glucose dependency 6–9 months after starting TDF/FTC.

Taken together, these results indicate that daily TDF/FTC PrEP can push innate immune cells toward a more activated, pro-inflammatory state and reprogram their metabolism even in the absence of HIV infection. That immunometabolic shift may help explain why people living with treated HIV show persistent inflammation and earlier onset of age-related conditions; this study suggests that the drugs themselves, not only the virus, can remodel immune pathways. At the same time, the heightened monocyte responses observed after bacterial challenge hint that ART exposure could enhance early defenses against pathogens like Mycobacterium tuberculosis, potentially altering susceptibility or disease course. For clinicians and researchers, the findings highlight the need to understand both beneficial and detrimental effects of ART in HIV-negative people on PrEP, and to consider how to optimise regimens to preserve protection while minimising unwanted inflammation. Future work will be needed to define long-term consequences and to explore strategies that retain PrEP’s prevention benefits without promoting chronic immune activation.