HIV-1 TAT INHIBITS HUMAN NATURAL-KILLER-CELL FUNCTION BY BLOCKING L-TYPE CALCIUM CHANNELS

Herein we show that functional phenylalkylamine-sensitive L-type calci um channels are expressed by human NK cells and are involved in the ki lling of tumor targets, Blocking of these channels by phenylalkylamine drugs does not affect effector/target cell binding but inhibits the r elease of serine esterases responsible for cytotoxicity. Interestingly , treatment of NK cells with HIV-1 Tat, which is known to affect sever al calcium-mediated events in immune cells, impairs their cytotoxic ac tivity. In addition, Tat inhibits the rise in intracellular free calci um concentration upon cross-linking of the adhesion molecule CD11a, en gaged during effector/target cell interaction, and the activation mole cule CD16, Exogenous Tat does not influence NK-target cell binding but prevents NK cell degranulation, We propose that the molecular structu re(s) on NK cells mediating the inhibitory effects HIV-1 Tat belong to L-type calcium channels, based on three lines of evidence: 1) binding of phenylalkylamine derivatives to these channels is cross-inhibited by Tat; 2) L-type calcium channels from NK cell lysates bind to Tat li nked to Sepharose columns; 3) the inhibitory effect of HIV-1 Tat on NK cell function is prevented by the agonist of L-type calcium channels, Bay K 8644, Altogether, these results suggest that exogenous Tat is d eeply involved in the impairment of NK cell function during HIV-1 infe ction.