The N-terminal Structure of HIV-1 Tat Is Required for Suppression of CD26-dependent T Cell Growth

Abstract

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 (DP IV) activity. Here we show that the N-terminal nonapeptide MDPVDPNIE of Tat is a competitive inhibitor of DP IV and suppresses DNA synthesis of tetanus toxoid-stimulated peripheral blood mononuclear cells. Amino acid exchanges at positions 5 and 6 strongly weaken these effects. 1H nuclear magnetic resonance and molecular dynamics simulations of Tat(1-9), I5-Tat(1-9), and L6-Tat(1-9) suggest a similar backbone conformation for Tat(1-9) and L6-Tat(1-9). The solution conformation of I5-Tat(1-9) considerably differs from the other two. However, Tat(1-9) fits into our previously proposed active site model of DP IV in contrast to I5-Tat(1-9) and L6-Tat(1-9). Conformational alterations with regard to the parent peptide and spatial hindrances between these both compounds and DP IV 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 DP IV and that DP IV does mediate Tat's immunosuppressive effects.

Tat Protein of Human Immunodeficiency Virus Type 1 Induces Interleukin-10 in Human Peripheral Blood Monocytes: Implication of Protein Kinase C-Dependent Pathway

“…In spite of this, the overall effect of Tat in patients infected by HIV-1 appears rather suppressive. This can be explained by the inhibition of the proliferative T response (52,56), the induction of T-lymphocyte apoptosis (26), the inhibition of phagocytosis of apoptotic bodies by dendritic cells (58), the cytotoxic activity of NK cells (59), and finally the suppression of IL-12 production by dendritic cells (45) and monocytes (31). The effect of Tat on IL-10 production reported here agrees with all of these reports concerning the potential immunosuppressive role of Tat during infection by HIV.…”

Tat-Neutralizing Antibodies in Vaccinated Macaques

“…The amino terminus (aa 1 to 20), cysteine-rich domain (aa 21 to 40), and core region (aa 1 to 48) together constitute the minimal activation domain for transcription in vitro (30). The N-terminal portion of Tat binds cell surface CD26 with high affinity and is believed to be responsible for CD26-mediated immunosuppressive activity (26,49,57). The cysteine-rich domain has homology to chemokines and mediates binding to chemokine receptors (1,2,16).…”

Identification of Specific Molecular Structures of Human Immunodeficiency Virus Type 1 Tat Relevant for Its Biological Effects on Vascular Endothelial Cells

“…By the use of peptides spanning specific domain of the Tat structure or of functional blocking antibodies, some investigators demonstrated that Tat binding to integrin through the RGD sequence near the C terminus (7,62) is relevant for the activation of lymphocytes (70), EC (5, 13), monocytes (6,35), and neuronal cells (48). Through its N-terminal structure, Tat interacts with dipeptidyl peptidase IV, located on the T cell surface, and suppresses antigen-induced cell activation (26,68). Additionally, Tat binds to and activates the tyrosine kinase receptors encoded by the KDR and Flt-1 genes in EC and Kaposi's sarcoma cells (4,21) and monocytes (43), respectively.…”