HIV-1 Tat Inhibits Human Natural Killer Cell Function by Blocking L-Type Calcium Channels

Abstract

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.

Correction: HIV-1 Tat Protein Induces the Production of IDO in Human Monocyte Derived-Dendritic Cells through a Direct Mechanism: Effect on T Cells Proliferation

“…Because this active domain lacks the basic region 47-57, which is essential for Tat internalization, we can deduce that Tat protein activates IDO production by acting at the cell membrane level. This conclusion is in agreement with several reports showing that Tat protein is able to bind to cell membrane and several receptors have been proposed by different groups, including avb3, and a5b1 [56], CD26 [57], CCR2, CCR3 [58] and CXCR4 [10], V-EGF and b-FGF [59] and L-Type calcium channel [60,61], and low density lipoprotein receptor-related protein [62].…”

A randomized clinical trial of alternative stress management interventions in persons with HIV infection.

“…NKC function may be of major prognostic significance in AIDS-related opportunistic infections. These cells spontaneously lyse virally infected cells but become functionally defective as HIV disease progresses (Chehimi et al, 1992; Hu et al, 1995; Zocchi, Rubartelli, Morgavi, & Poggi, 1998). NKC cytotoxicity was evaluated in a standard 4-hr chromium ( 51 Cr) release assay with NKC-sensitive K562 cells (American Type Culture Collection; ATCC, Manassas, VA) as targets.…”

La protéine Tat du VIH-1 induit la production d’IL-10 par le monocyte humain : implication de la voie PKC et de la voie calcique

“…Des travaux récents ont montré que la protéine Tat agit sur le signal calcique à plusieurs niveaux (Rubartelli et al, 1998). Elle est capable de se lier et ainsi, de bloquer les canaux cal ciques voltage dépendants de type L dans les cellules dendritiques (Poggi et al, 1998) et dans les cellules NK (Zocchi et al, 1998). Il a été aussi montré que la région 24-51 de Tat est capable d'induire un signal calcique chez le monocyte/macrophage en mimant le rôle de cer taines chimiokines et ainsi jouant un rôle dans la chimioattraction des neutrophiles (Albini et al, 2000).…”