Beyond Viral Control: Tenofovir's Hidden Impact on Blood–Brain Barrier Endothelial Cells

ABSTRACT The blood–brain barrier (BBB) is a dynamic endothelial interface that protects the brain from harmful agents while regulating molecular exchange. Human immunodeficiency virus (HIV) compromises BBB integrity, promoting neurological damage. Antiretroviral (ARV) therapies suppress HIV replication, preventing immune system deterioration and progression to AIDS. Although Tenofovir‐based ARV regimens are vital for HIV treatment and prevention, their impact on cerebrovascular function remains unclear. Aim This study examined Tenofovir's effects on murine brain endothelial cells using an in vitro BBB model. Methods Brain endothelial cells (bEnd.5) were treated with Tenofovir Disoproxil Fumarate (TDF; 9.8–98 ng/mL) or Tenofovir Alafenamide (TAF; 1–10 ng/mL) for 24–96 h. Cell proliferation, cell cycle progression (via flow cytometry) and monolayer permeability (via Transendothelial Electrical Resistance) were evaluated. Results Both TDF and TAF treatments suppressed cell division by S‐phase disruption of the cell cycle and increased monolayer permeability. Conclusion These findings suggest that prolonged TDF or TAF exposure compromises BBB integrity by inhibiting endothelial cell division and altering barrier function, which could have implications for HIV‐ARV‐induced neurodegeneration in individuals receiving long‐term Tenofovir‐based therapy.