HIV-1 Tat triggers TGF-beta production and NK cell apoptosis that is prevented by pertussis toxin B.
Herein, we show that PTX-B and its non-toxic mutant PT9K/129G inhibit transcription and secretion of TGF-beta elicited by HIV-1 Tat in NK cells. Moreover, Tat strongly activates the cJun component of the multimolecular complex AP-1, while TGF-beta triggers cFos and cJun. Treatment of NK cells In turn,with PTX-B or PT9K/129G inhibits Tat and TGF-beta-induced activation of AP-1. TGF-beta 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-beta-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-beta and Tat were detected in the sera of these patients. These data suggest that Tat-induced TGF-beta production and the consequent NK cell failure, possibly occurring during early HIV-1 infection, may be regulated by PTX-B and PT9K/129G.
Poggi
Alessandro
A
Laboratory of Experimental Oncology D, National Institute for Cancer Research, Genoa, Italy. alessandro.poggi@istge.it
Zocchi
Maria Raffaella
MR
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015696:Gene Products, tat / Q000494:pharmacology*; D015658:HIV Infections / Q000276:immunology / Q000473:pathology; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D037342:Pertussis Toxin / Q000276:immunology / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D016212:Transforming Growth Factor beta; D054322:tat Gene Products, Human Immunodeficiency Virus; D037342:Pertussis Toxin