HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals

A highly conserved signaling property of Nef proteins encoded by human or s imian immunodeficiency virus is the binding and activation of a PAK kinase whose function is unclear. Here we show that Nef-mediated p2l-activated kin ase (PAK) activation involves phosphatidylinositol 3-kinase, which acts ups tream of PAK and is bound and activated by Nef similar to the manner of Pol yoma virus middle T antigen. The Nef-associated phosphatidylinositol-3-PAK complex phosphorylated the pro-apoptotic Bad protein without involving the protein kinase B-Akt kinase, which is generally believed to inactivate Bad by serine phosphorylation. Consequently, Nef, but not a Nef mutant incapabl e of activating PAK, blocked apoptosis in T cells induced by serum starvati on or HIV replication. Nef anti-apoptotic effects are likely a crucial mech anism for viral replication in the host and thus in AIDS pathogenesis.