HIV-1 Tat inhibits human natural killer cell function by blocking L-type calcium channels.
Herein we show that functional phenylalkylamine-sensitive L-type calcium channels are expressed by human NK cells and are involved in the killing of tumor targets. Blocking of these channels by phenylalkylamine drugs does not affect effector/target cell binding but inhibits the release of serine esterases responsible for cytotoxicity. Interestingly, treatment of NK cells with HIV-1 Tat, which is known to affect several calcium-mediated events in immune cells, impairs their cytotoxic activity. In addition, Tat inhibits the rise in intracellular free calcium concentration upon cross-linking of the adhesion molecule CD11a, engaged during effector/target cell interaction, and the activation molecule CD16. Exogenous Tat does not influence NK-target cell binding but prevents NK cell degranulation. We propose that the molecular structure(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 linked 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 deeply involved in the impairment of NK cell function during HIV-1 infection.
Zocchi
M R
MR
Laboratory of Tumor Immunology, Scientific Institute San Raffaele, Milan, Italy.
Rubartelli
A
A
Morgavi
P
P
Poggi
A
A
D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004950:Esterases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015696:Gene Products, tat / Q000502:physiology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D015696:Gene Products, tat; D007166:Immunosuppressive Agents; D054322:tat Gene Products, Human Immunodeficiency Virus; D004950:Esterases; C022635:serine esterase