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

Abstract

A highly conserved signaling property of Nef proteins encoded by human or simian immunodeficiency virus is the binding and activation of a PAK kinase whose function is unclear. Here we show that Nef-mediated p21-activated kinase (PAK) activation involves phosphatidylinositol 3-kinase, which acts upstream of PAK and is bound and activated by Nef similar to the manner of Polyoma 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 incapable of activating PAK, blocked apoptosis in T cells induced by serum starvation or HIV replication. Nef anti-apoptotic effects are likely a crucial mechanism for viral replication in the host and thus in AIDS pathogenesis.

HIV-1 Nef Promotes Survival of TF-1 Macrophages by Inducing Bcl-X Expression in an Extracellular Signal-regulated Kinase-dependent Manner

“…Recent studies have shown that Nef inhibits death receptor-mediated apoptosis by interacting with apoptosis signal regulating kinase 1 and blocking its activity in T cells (12). More recently, it has been demonstrated that HIV-1 Nef also suppresses apoptosis by stimulating Akt-independent Bad phosphorylation through PI3K and PAK pathways in T lymphocytes (13). In contrast to these studies, we found that Nef-induced survival does not require PI3K activity (Fig.…”

“…In addition, Nef suppresses T-cell apoptosis initiated by serum starvation or HIV replication. In this case, Nef was shown to induce serine phosphorylation of Bad, the mitochondrial pro-apoptotic mediator, through a previously described p21-activated protein kinase known to associate with Nef (13).…”

“…Recent work has shown that anti-apoptotic signaling by HIV-1 Nef involves the PI3K pathway in T cells (13). To examine whether PI3K also contributes to Nef survival signaling in myeloid cells, we tested the effect of a specific PI3K inhibitor, LY294002 (24), on cell survival induced by Nef in the TF-1 model system.…”

The Glutamine-rich Region of the HIV-1 Tat Protein Is Involved in T-cell Apoptosis

“…It is not plausible that HIV has evolved a highly specific mechanism by which Tat kills off only bystander cells; thus, it is possible that two HIV-encoded proteins control the activities of the main regulators of the mitochondrial apoptotic pathway in infected cells. HIV-1 Nef activates the phosphatidylinositol 3-kinase⅐p21-activated kinase complex, which inactivates the pro-apoptotic Bad protein by phosphorylation (70), and HIV-1 Vpr activates the down-modulation of the pro-apoptotic Bax protein and up-regulates the levels of the anti-apoptotic Bcl-2 protein (71). Thus, Nef and Vpr possibly counteract the effects of Tat in infected cells and protect the infected cells from apoptosis.…”

Pro-apoptotic Activity of HIV-1 Auxiliary Regulatory Protein Vpr Is Subtype-dependent and Potently Enhanced by Nonconservative Changes of the Leucine Residue at Position 64

“…Nef produced during HIV replication enhances expression of the Fas ligand (FasL) on the surface of infected cells, causing apoptosis of bystander cells through FasL-Fas cross-linking (9). On the other hand, Nef protects the infected cells from apoptosis by inhibition of the apoptosis signal-regulating kinase 1 (ASK1) or inhibition of the proapoptotic protein Bad through increased phosphorylation by the p21-activated kinase (10,11).…”