HIV‐1 Tat Triggers TGF‐β Production and NK Cell Apoptosis that is Prevented by Pertussis Toxin B

Abstract

Herein, we show that PTX-B and its non-toxic mutant PT9K/129G inhibit transcription and secretion of TGF-b elicited by HIV-1 Tat in NK cells. Moreover, Tat strongly activates the cJun component of the multimolecular complex AP-1, while TGF-b triggers cFos and cJun. Treatment of NK cells In turn,with PTX-B or PT9K/129G inhibits Tat and TGF-b-induced activation of AP-1. TGF-b enhances starvation-induced NK cell apoptosis, reduces the transcription of the antiapoptotic protein Bcl-2 and inhibits Akt phosphorylation induced by oligomerization of the triggering NK cell receptor NKG2D. All these TGF-b-mediated effects are prevented by PTX-B or PT9K/129G, through a PI-3K-dependent mechanism. Finally, PTX-B and PT9K/129G upregulate Bcl-x L , the isoform of Bcl-x that protects cells from starvation-induced apoptosis. Of note, in NK cells from patients with HIV-1 infection, mRNA expression of Bcl-2 and Bcl-x L was consistently lower than that of healthy donors; interestingly, TGF-b and Tat were detected in the sera of these patients. These data suggest that Tat-induced TGF-b production and the consequent NK cell failure, possibly occurring during early HIV-1 infection, may be regulated by PTX-B and PT9K/129G.

Altered distribution of mucosal NK cells during HIV infection

“…Interestingly, this NK cell expansion is not observed in chronic untreated patients, despite the fact that they exhibit reduced CD4+ T cell numbers as well, however, these individuals also exhibit high levels of viral replication and persistent immune activation, due to microbial translocation 8 , through accessory cells 40 . This hyper-activation, however, may drive direct NK cell apoptosis 47 , thereby preventing the observed increase of these cytolytic effector cells within tissues.…”

Functions of Tat: the versatile protein of human immunodeficiency virus type 1

“…The transactivating effects of Tat are not limited to HIV-1-infected cells because the extracellular Tat protein, released from virus-infected cells, is able to enter uninfected cells and exert its activity directly on responsive genes (Ju et al, 2009). The upregulation of cellular genes by Tat consequently induces additional effects, such as apoptosis induction and immunosuppression (Gupta et al, 2008;Poggi & Zocchi, 2006;Bannasser & Bahraoui, 2002;Zheng et al, 2005), which will be discussed later.…”

“…Gupta et al (2008) have shown that Tat suppresses gp120-specific T-cell response in an IL-10-dependent manner and the immunosuppressive effect of Tat is not observed in IL-10-deficient mice. Although they have suggested that the immunosuppressive effect of Tat is mediated through IL-10, it seems that Tat may adopt several strategies to suppress the immune system of HIVinfected individuals (Barton et al, 1996;Gallo, 1999;Miura et al, 2003;Poggi & Zocchi, 2006;Zheng et al, 2005).…”

“…The upregulation of TGF-b transcription by Tat has been claimed to contribute to immunosuppression in AIDS (Poggi & Zocchi, 2006). TGF-b has been reported to induce apoptosis in several cell types through AP-1-dependent activation of the src homology 2 (SH2)-domain containing inositol-5-phosphatase (Licona-Limó n & Soldevila, 2007; Tarasenko et al, 2007).…”

“…The upregulation of TGF-b by Tat reduces antiapoptotic proteins and thereby renders immune cells vulnerable to apoptosis. The outcome of this event could be the induction of immunosuppression (Poggi & Zocchi, 2006).…”