HIV-1 Tat: a polypeptide for all seasons

doi:10.1016/S0167-5699(98)01351-6

Immunology Today

Volume 19, Issue 12, 1 December 1998, Pages 543-545

Immunology Today

https://doi.org/10.1016/S0167-5699(98)01351-6 Get rights and content

Abstract

A plethora of mechanisms of action have been proposed for exogenous Tat to explain the pleiotropic, and sometimes controversial, extracellular effects reported for this molecule. Anna Rubartelli and colleagues discuss the molecular bases of these multiple functions.

Section snippets

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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TrendsHIV-1 Tat: a polypeptide for all seasons

Abstract

Section snippets

Extracellular HIV-1 Tat: beyond viral infection

A secret weapon towards the paralysis of the immune system

How can a small protein exert so many functions?

L-type Ca2+ channels: a common molecular target?

The importance of defining Tat molecular structure

Acknowledgements

J. Mol. Biol.

Blood

J. Biol. Chem.

Cell

J. Biol. Chem.

Cell

Biophys. J.

Trends Neurosci.

Nat. Med.

Nature

Oncogene

Nat. Med.

Trends
HIV-1 Tat: a polypeptide for all seasons

L-type Ca²⁺ channels: a common molecular target?