Grb3-3 is up-regulated in HIV-1-infected T-cells and can potentiate cell activation through NFATc

The MAPK pathway is required for T-cell activation; however, its role in mo dulating T-cell function following human immunodeficiency virus type 1 (HIV -1) infection is poorly understood. In this report, we investigated whether Grb3-3, an isoform of the Grb2 (growth factor receptor-bound protein-2) ad aptor molecule that is associated with the MAPK pathway, could be involved. We found that Grb3-3, but not its isoform Grb2, is markedly up-regulated i n CD4(+) peripheral blood mononuclear cells derived from either in vitro HI V-1-infected cultures or HIV-1-infected human subjects. Analysis of HIV-1 g ene products indicated that Tat and Nef, both of which have been implicated in modulating T-cell function, can independently induce expression of Grb3 -3. By using NFAT/AP-1, AP-1, or NFAT reporter assays, we found that Grb3-3 can potentiate NFAT (but not AP-1) promoter activity in Jurkat T-cells upo n engagement of the T-cell receptor and CD28 co-receptor. In addition, pote ntiation of NFAT by Grb3-3 is substantially suppressed by MEKK1, a kinase t hat may play an important role in retaining NFAT in the cytoplasm, and by c yclosporin A. Finally, we also found that Grb3-3 potentiates HIV-1 long ter minal (LTR) repeat promoter activity following T-cell receptor stimulation, an effect that can be largely suppressed by cyclosporin A. Taken together, this study indicates that Grb3-3 is a cellular factor that can be up-regul ated by HIV-1. In addition, Grb3-3 can also function as a positive factor f or T-cell activation and, in doing so, may aid in establishing an intracell ular environment that can optimally support HIV-1 replication.