he clinical consequences of human immunodeficiency virus type-1 (HIV-1) infection are mainly due to the ability of this virus to disarm the immune system. As a retrovirus, HIV-1 can latently infect host cells and replicate with a fairly low mutation rate, thus remaining hidden for a long time. To overcome the immune surveillance, HIV- 1 seems to use several tools, including viral and host cell products. In addition to struc- tural and enzymatic proteins, HIV-1 encodes a group of at least six auxiliary regulatory proteins. These include Tat, an 86–104 amino acid protein essential for HIV-1 replication (reviewed in Ref. 1). Tat is encoded by two exons, the first of which contributes the N- terminal 72 residues. The Tat sequence can be subdivided into different regions: a cys- teine-rich domain (amino acids 20–31), a core region (amino acids 32–47), a basic re- gion (amino acids 48–57) containing the nu- clear localization sequence, which is highly conserved among viral Tat proteins, and a glutamine-rich region (amino acids 60–76). The role of the cysteine-rich domain is un- clear, but the core, basic and glutamine-rich regions are all involved in RNA binding 2 . Despite its nuclear localization and function and the lack of any secretory signal se- quence, Tat seems to be secreted by infected cells 3 , thus joining the growing family of leaderless secretory proteins released by nonclassical mechanisms of secretion, which play a role extra- and/or transcellularly 4 . Extracellular HIV-1 Tat: beyond viral infection That Tat is released by infected cells is sup- ported by the detection of the protein in sera of patients with acquired immune defi- ciency 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 nonim- mune and immune dysfunctions during AIDS. One important target of exogenous Tat is normal or transformed vascular endo- thelium: Tat supports endothelial cell spreading and induces angiogenesis and in- flammation, possibly contributing to the de- velopment of Kaposi’s sarcoma 3,5,6 . Another effect of exogenous Tat is cytotoxicity: Tat induces apoptosis in T cells 1 and cell death in neurons 7 . Furthermore, Tat can be taken up by bystander cells, reach their nucleus and transactivate several viral or cellular genes. Among host genes, Tat can drive transcription of a number of cytokines, such as interleukin 6 (IL-6), IL-2 and tumor necrosis factor  (Ref. 1), and of endothelial adhesion molecules, such as intercellular adhesion molecule 1 and vascular cell adhe- sion molecule 1 (Ref. 8). Thus, some of the reported effects of Tat may be mediated by Tat-induced cytokines or, possibly, chemokines. Finally, Tat seems to induce oxi- dative stress and alter the reduced:oxidized glutathione ratio in target cells, thus poten- tiating cytokine-mediated activation of NF-B (Ref. 9). A secret weapon towards the paralysis of the immune system The upregulation of inflammatory and im- munostimulatory cytokines 1 and of mol- ecules involved in monocyte chemotaxis 8 would suggest an activating role of Tat on the immune system. However, several im- munosuppressive functions have been at- tributed to exogenous Tat, which may ac- count for the net effect of immune depression in AIDS patients. Indeed, in ad- dition to inducing T-cell apoptosis, Tat in- hibits both antigen-driven and nonspecific T-cell proliferation 10,11 . Tat inhibits the phagocytosis of apoptotic tumor cells by ac- cessory cells 12 , possibly leading to defective processing and presentation of tumor-asso- ciated antigens, and prevents secretion of IL-12 (Ref. 13), a cytokine known to stimu- late natural killer (NK) cells and to drive the differentiation of the T helper (Th) 1 cell subset. Thus, the inhibition of apoptotic body engulfment may contribute to defec- tive anti-tumor immune surveillance; in turn, the impairment of IL-12 production may contribute to the decrease in NK-cell activity and to the Th1–Th2 imbalance ob- served in AIDS patients 14 . Finally, Tat in- hibits both spontaneous and CD16-induced killing of tumor targets by NK cells, appar- ently through blocking granzyme A secre- tion 15 . All these effects might contribute to the impairment of natural immunity in AIDS and to the reduction of the immune response to foreign antigens. 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 de- fined extracellular functions. (1) The basic region has been reported to alter angiogen- esis, leading to Kaposi’s sarcoma, through the interaction with low-affinity (heparan sulphates) and high-affinity (vascular en- dothelial growth factor receptor) binding sites on target cells 5,6 . (2) In addition, the basic segment mediates the entry of Tat into target cells 16 via a partially characterized mechanism 17 and targets the internalized molecule to the nucleus. (3) Tat RGD tripep- tide (amino acids 78–80) binds  v  3 and  5  1 integrins 18 . This interaction results in the inhi- bition of apoptotic body engulfment by den- dritic cells (DCs) 12 , and in the induction of en- dothelial cell spreading 19 . (4) The neurotoxic effects of Tat seem to be sustained by amino acids 31–61 (Ref. 7); a partially overlapping peptide (amino acids 24–51) is involved in Vol.19 No.12 543 TRENDS IMMUNOLOGY TODAY 0167-5699/98/$ – see front matter © 1998 Elsevier Science. All rights reserved. PII: S0167-5699(98)01351-6 DECEMBER 1998 HIV-1 Tat: a polypeptide for all seasons Anna Rubartelli, Alessandro Poggi, Roberto Sitia and M. Raffaella Zocchi 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. T