TrendsHIV-1 Tat: a polypeptide for all seasons
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Extracellular HIV-1 Tat: beyond viral infection
That Tat is released by infected cells is supported by the detection of the protein in sera of patients with acquired immune deficiency syndrome (AIDS), in the absence of a massive lysis of infected cells[1]. Furthermore, there is now increasing evidence for a role of extracellular Tat in many pathological processes, which may contribute to nonimmune and immune dysfunctions during AIDS.
One important target of exogenous Tat is normal or transformed vascular endothelium: Tat supports endothelial
A secret weapon towards the paralysis of the immune system
The upregulation of inflammatory and immunostimulatory cytokines[1]and of molecules involved in monocyte chemotaxis[8]would suggest an activating role of Tat on the immune system. However, several immunosuppressive functions have been attributed to exogenous Tat, which may account for the net effect of immune depression in AIDS patients. Indeed, in addition to inducing T-cell apoptosis, Tat inhibits both antigen-driven and nonspecific T-cell proliferation10, 11. Tat inhibits the phagocytosis of
How can a small protein exert so many functions?
Mainly by analysing sets of overlapping peptides, it has been possible to identify specific sequences of Tat that mediate defined extracellular functions. (1) The basic region has been reported to alter angiogenesis, leading to Kaposi's sarcoma, through the interaction with low-affinity (heparan sulphates) and high-affinity (vascular endothelial growth factor receptor) binding sites on target cells5, 6. (2) In addition, the basic segment mediates the entry of Tat into target cells[16]via a
L-type Ca2+ channels: a common molecular target?
Most of the immune cell functions impaired by exogenous Tat are tightly dependent on variations in the intracellular Ca2+ levels. In particular, the entry of extracellular Ca2+ is needed for the progression of antigen-specific or nonspecific T-cell proliferation[21], for DC phagocytosis[12]and for NK-cell activity[15]. In excitable tissues the influx of Ca2+ is mediated mainly by L-type Ca2+ channels: these comprise four transmembrane subunits (α1, α2, γ and δ) responsible for the pore-forming
The importance of defining Tat molecular structure
Several controversial and sometimes opposite effects of exogenous Tat on target cells has been observed. For instance, Tat has been reported to exert either activatory or inhibitory effects on T cells in vitro depending on how it is administered (soluble or immobilized)[26]. This finding, together with the difficulties encountered in the crystallization of the molecule, suggests that Tat conformation is highly unstable. Indeed, an interesting feature emerging from NMR and MD analyses[2]is that,
Acknowledgements
We thank our colleagues for helpful discussions. Work in our laboratories is supported by grants from AIRC, CNR (PF Biotecnologie) and ISS (special project AIDS).
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2015, Journal of Biological ChemistryCitation Excerpt :Despite the lack of a signal peptide, secretion of HIV-Tat was shown to occur independent of cell damage and, therefore, HIV-Tat was classified as a protein secreted by unconventional means (5, 8, 11, 41, 49–51). Extracellular HIV-Tat is supposed to be essential for viral spread and plays an important role in AIDS pathogenesis by modulating the immune response (49–51). Recent studies indicate that vaccination with anti-Tat antibodies slows down AIDS progression and may restore immune functions (52–54).