Upregulation of the apoptosis-associated protein Grb3-3 in HIV-1-infected human CD4(+) lymphocytes

The mechanism(s) by which HIV-1 infection contributes to depletion of CD4() T cell is not well understood. In this report, we investigated whether a recently identified isoform of growth factor receptor bound protein (Grb2), named Grb3-3, a signaling molecule that is associated with the MAP kinase pathway and with apoptosis could be involved. We find that Grb3-3 is marked ly up-regulated following HIV-1infection of CD4(+) peripheral blood mononuc lear cells undergoing apoptosis. Although IL-2 deprived CD4(+) cells also u ndergo apoptosis to a similar extent, Grb3-3 upregulation is not detected u nder these experimental conditions. Transient overexpression of Grb3-3 in J urkat T-cells also causes apoptosis. Upon staurosporine stimulation, Grb3-3 predisposes Sup-T1 cell to apoptosis. Finally, analysis of the HIV-1genes responsible for Grb3-3 expression demonstrates that Tat and Nef can indepen dently induces its expression, suggesting these two earliest viral gene pro ducts of HIV-1 may share some common pathway(s) in up-regulating Grb3-3 exp ression. (C) 2000 Academic Press.