INVOLVEMENT OF EXTRACELLULAR SIGNAL-REGULATED KINASE MODULE IN HIV-MEDIATED CD4 SIGNALS CONTROLLING ACTIVATION OF NUCLEAR FACTOR-KAPPA-B AND AP-1 TRANSCRIPTION FACTORS

Although the molecular mechanisms by which the HIV-1 triggers either T cell activation, anergy, or apoptosis remain poorly understood, it is well established that the interaction of HIV-1 envelope glycoproteins with cell surface CD4 delivers signals to the target cell, resulting in activation of transcription factors such as NF-kappa B and AP-1. In this study, we report the first evidence indicating that kinases MEK- 1 (MAP kinase/Erk kinase) and ERK-1 (extracellular signal-regulated ki nase) act as intermediates in the cascade of events that regulate NF-k appa B and AP-1 activation upon HIV-1 binding to cell surface CD4. We found that CEM cells transfected with dominant negative forms of MEK-1 or ERK-1 do not display NF-kappa B activation after HIV-1 binding to CD4. In contrast, NF-kappa B activation was observed in these cells af ter PMA stimulation. Although the different cell lines studied express ed similar amounts of CD4 and p56(lck), HIV-1 replication and HIV-1-in duced apoptosis were slightly delayed in cells expressing dominant neg ative forms of MEK-1 or ERK-1 compared with parental CEM cells and cel ls expressing a constitutively active mutant form of MEK-1 or wild-typ e ERK-1, In light of recently published data, we propose that a positi ve signal initiated following oligomerization of CD4 by the virus is l ikely to involve a recruitment of active forms of p56(lck), Raf-1, MEK -1, and ERK-1, before AP-1 and NF-kappa B activation.