In addition to the stimulation of HIV-1 transcription, Tat protein, which is secreted by the infected cells, exerts pleiotropic effects on uninfected bystander cells. This seems to be mediated by the interaction between Tat protein and extracellular Notch receptor. Co-immunoprecipitation and GST pull-down assay have revealed the interaction between HIV-1 Tat and hN2E1~6 (human Notch2 EGF-like repeats 1~6). Treatment of Tat protein interfered with Notch signaling in Jurkat cells in which the expression of Notch receptor and ligand are abundant. Dose dependent transcriptional repression of Notch responsive HES-1 gene was observed in Tat treated Jurkat cells.