HIV-1 Tat inhibits IL-2 gene transcription through qualitative and quantitative alterations of the cooperative Rel/AP1 complex bound to the CD28RE/AP1 composite element of the IL-2 promoter

Dysregulation of cytokine secretion plays an important role in AIDS pathoge nesis. Here, we demonstrate that expression of HIV-1 Tat protein in Jurkat cells induces a severe impairment of IL-2 but not TNF gene transcription. I nterestingly, this inhibition correlates with the effect of the viral prote in on the transactivation of the CD28RE/AP1 composite element (-164/-154), but not with that observed on the NFAT/AP1 site of the IL-2 gene promoter, neither with the effect on NF-kappaB- nor AP1-independent binding sites. En dogenous expression of Tat induced a decrease in the amount of the specific protein complex bound to the CD28RE/AP1 probe after PMA plus calcium ionop hore stimulation. This effect was accompanied by qualitative alterations of the API complex. Thus, in wild-type Jurkat cells, e-jun was absent from th e complex, whereas in Tat-expressing cells, c-jun was increasingly recruite d overtime. By contrast, similar amounts of c-rel and a small amount of NFA T1 were detected both in wild type and in Jurkat Tat(+) cells. Furthermore, Tat not only induced the participation of c-jun in the cooperative complex but also a decrease in its transactivation activity alone or in combinatio n with c-rel. Thus, the interaction of Tat with the components of this rel/ AP1 cooperative complex seems to induce quantitative and qualitative altera tions of this complex as activation progresses, resulting in a decrease of IL-2 gene transcription. Altogether our results suggest the existence of tu ned mechanisms that allow the viral protein to specifically affect cooperat ive interactions between transcription factors.