CYCLOSPORINE-A SENSITIVITY OF THE HIV-1 LONG TERMINAL REPEAT IDENTIFIES DISTINCT P56LCK-DEPENDENT PATHWAYS ACTIVATED BY CD4 TRIGGERING

The CD4 co-receptor interacts with nonpolymorphic regions of major his tocompatibility complex class II molecules on antigen-presenting cells . This interaction results in the mobilization of a number of signalin g mediators shared by the T cell receptor (TcR) signaling pathway and thus amplifies TcR-generated signals. We have investigated the outcome of CD4 engagement on the activation of both cellular transcription fa ctors and the HIV-1 long terminal repeat (LTR). We show that CD3 trigg ering activates different pathways of HIV LTR activation which can be identified by their sensitivity to the immunosuppressant cyclosporin A . The response of the inducible cellular transcription factors involve d in HIV LTR activation shows that both nuclear factor (NF)-kappa B an d NF-AT mediate a cyclosporin A-sensitive response to CD4, while AP-1 is at least in part responsible for the cyclosporin A-insensitive resp onse. Both pathways can, however, be blocked by a kinase-defective dom inant negative p56lck mutant, supporting an essential role for p56lck kinase activity in CD4-dependent signal transduction. A functional ana lysis of different CD4 epitopes using either anti-CD4 mAb or HIV-1 gp1 20 reveals a common epitope-specific activation of both the LTR and of the transcription factors NF-kappa B and NF-AT.