HIV-1 Nef Interacts with Inositol Trisphosphate Receptor to Activate Calcium Signaling in T Cells

HIV-1 pathogenicity factor Nef has been shown to modulate calcium signaling in host cells, but the underlying molecular mechanisms have remained unclear. Here we show that calcium/calcineurin-dependent activation of nuclear factor of activated T cells (NFAT) by Nef in Jurkat T cells requires the endoplasmic reticulum-resident inositol trisphosphate receptor (IP₃R), but yet does not involve increase in phospholipase-Cγ1 (PLCγ1)-catalyzed production of IP₃ or depletion of IP₃-regulated intracellular calcium stores. Nef could be coprecipitated with endogenous IP₃R type-1 (IP₃R1) from Nef-transfected Jurkat T cells as well as from HIV-infected primary human peripheral mononuclear cells. Thus, the Nef/IP₃R1-interaction defines a novel T cell receptor–independent mechanism by which Nef can promote T cell activation, and appears to involve atypical IP₃R-triggered activation of plasma membrane calcium influx channels in a manner that is uncoupled from depletion of intracellular calcium stores.