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

Aki Manninen¹ and Kalle Saksela^1,2

¹ Institute of Medical Technology, University of Tampere, Tampere FIN-33014, Finland
² Department of Clinical Chemistry, Tampere University Hospital, Tampere FIN-33014, Finland

Address correspondence to Kalle Saksela, Institute of Medical Technology, University of Tampere, Tampere FIN-33014, Finland. Phone: 358-3-215 7029; Fax: 358-3-215 8597; E-mail: kalle.saksela{at}uta.fi

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-C1 (PLC1)-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.

Key Words: accessory protein • capacitative calcium entry • IL-2 • NFAT • T cell activation

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