HIV tat binds Egr proteins and enhances Egr-dependent transactivation of the Fas ligand promoter

HIV Tat can enhance activation-induced up-regulation of Fas ligand (Fast,), which may contribute to T cell apoptosis in human immune deficiency virus (HIV)-infected individuals. We have assessed functional and physical interactions between Tat and the Egr family of transcription factors (Egr-1, -2, and -3), the latter two of which are major participants in activation-induced Fast, up-regulation. Here we report that whereas Tat itself has no effect on the Fast, promoter, it binds to Egr-2 and -3 and synergizes with them to superinduce expression of a Fast, promoter-driven reporter. A Tat molecule containing a single amino acid substitution that results in the loss of transactivation activity for the HIV long terminal repeat still binds Egr-3 but can no longer enhance Egr-mediated transactivation of the Fast, promoter. Furthermore, the mutated Tat acts as a dominant negative inhibitor, blocking the superinduction of Fast, caused by wild type Tat. Because Tat is present in virus-infected cells and in the serum of HIV-infected individuals, these results suggest that increased expression of Fast, in these circumstances may result from the cooperative activities of activation-induced Egrs and Tat.