Nef is a multifunctional gene of HIV which can increase virus replication either directly or by modulating the target cell's metabolism. Nevertheless the role of the exogenous Nef protein is not yet well understood. To investigate it, we studied the effects of the recombinant Nef protein on the expression of some antigens of lymphoid T-cells permissive to HIV-1 replication, and on their proliferation and on apoptosis induction. For this purpose, we utilised MT-4 and H9 T-cell lines. We evaluated FN (fibronectin), CD4 and CD71 expression in uninfected and acutely or chronically infected cells, both untreated and treated with Nef. Our studies showed a significant up-regulation of FN especially in uninfected cells, with a dose of 2.5 microg ml(-1); in contrast, a significant down-modulation of CD4 and CD71 both in uninfected and in acutely or chronically infected cells, was detected. The proliferation of H9 uninfected cells was significantly reduced 24 h after treatment with Nef protein in a dose-dependent manner (ranging from 0.02 to 2.5 microg ml(-1)); likewise a significant inhibition of proliferation of acutely and chronically infected cells was evident with 2.5 microg ml(-1). Moreover, we demonstrated a dose-dependent activity of Nef on inducing apoptosis in H9 uninfected cells and no effects of this protein on modulation of INF alpha and gamma production in peripheral blood mononucleated cells of health donors. Nef appeared to be able to increase the effect of apoptotic stimuli. In conclusion, our data suggest that in our experimental system, the exogenous Nef protein can inhibit cellular synthesis facilitating the metabolic pathway involved in virus replication. In addition it modulates the susceptibility to the HIV-1 infection and finally, that apoptosis induction or enhancement can facilitate the release of neoformed virions.