The N-terminal structure of HIV-1 Tat is required for suppression of CD26-dependent T cell growth

Evidence exists that the human immunodeficiency virus-1 (HIV-1) transactivator Tat occurs extracellularly and is involved in the immunosuppression of non-HIV-1-infected T cells of acquired immunodeficiency syndrome (AIDS) patients, The mechanism of this immunosuppressive activity of Tat has been controversially discussed, Interestingly, Tat binds to the T cell activation marker CD26, which has been shown to play a key role in the regulation of growth of lymphocytes and to inhibit its dipeptidyl peptidase IV (DpIV) activity, Here we show that the N-terminal nonapeptide MDPVDPNIE of Tat is a competitive inhibitor of DP TV and suppresses DNA synthesis of tetanus toxoid-stimulated peripheral blood mononuclear cells, Amino acid exchanges at positions 5 and 6 strongly weaken these effects. H-1 nuclear magnetic resonance and molecular dynamics simulations of Tat(1-9), I-5-Tat(1-9), and L-6-Tat(1-9) suggest a similar backbone conformation for Tat(1-9) and L-6-Tat(1-9). The solution conformation of I-5-Tat(1-9) considerably differs from the other two. However, Tat(1-9) fits into our previously proposed active site model of DP TV in contrast to I-5-Tat(1-9) and L-6-Tat(1-9), Conformational alterations with regard to the parent peptide and spatial hindrances between these both compounds and DP TV can explain the loss of inhibitory activity. Our data suggest that the N-terminal residues of HIV-1 Tat do interact directly with the active site of DPIV and that DP TV does mediate Tat's immunosuppressive effects.