Nef: multi-tasker and sitting duck?

The genomes of lentiviruses are characterized by a number of accessory genes that, in addition to the gag–pol–env make-up of basic retroviruses, are thought to provide a complex and refined level of control in the viral life cycle.A unique feature of primate immunodeficiency viruses (HIV-1, HIV-2 and SIV) is the nef gene, which encodes the largest auxiliary protein. Although Nef proteins are highly variable, they all harbour conserved proline motifs and are N-terminally myristoylated. The function of Nef is critically important in vivo and there is a strong selective pressure for its maintenance. Recently, it has been demonstrated that Nef exerts at least four distinct activities. These include: (1) the downregulation of cell-surface CD4; (2) the downregulation of class 1 major histocompatibility antigens (MHC class 1); (3) enhanced viron infectivity; and (4) the upregulation of cell-surface Fas ligand. Numerous studies also indicate that it plays a role in cellular signal transduction and activation.Evidence for the ability of Nef to modulate signalling events in human cells is strong, and functional associations with a variety of intracellular kinases including Lck and Hck have been reported. Hck is rapidly induced following macrophage activation, and this induction has been implicated in signalling events controlling phagocytosis. This paper1xInduction of activator protein 1 (AP-1) in macrophages by human immunodeficiency virus type-1 NEF is a cell type specific response that requires both Hck and MAPK signalling events. Biggs, T.E. et al. J. Mol. Biol. 1999; 290: 21–35Crossref | PubMed | Scopus (47)See all References1 investigates the potential of Nef expression to modulate intracellular signalling events in macrophages. The central finding of this work is that in macrophages, Nef can induce the transcription factor AP-1 and AP-1-responsive genes, through interaction with Hck, and signal transduction through the mitogen-activated protein kinase (MAPK) pathway. Ultimately, this not only enhances viral replication in these cells, via transactivation of the HIV-1 promoter, but also modulates the expression of cellular genes. Interestingly, at least three other viral proteins (hepatitis B virus X protein, the polyoma middle T antigen and the Epstein–Barr virus latent membrane protein-1) modulate AP-1 activity via a similar signal transduction route, suggesting the importance of AP-1 transcriptional activation in these viral infections too. In HIV-1 infected macrophages, it is possible that the increased transcriptional activity could contribute to AIDS pathogenesis, by prolonging the life of these virus-producing cells and contributing to macrophage infection of the brain, leading to AIDS dementia complex. This work highlights the importance of Nef as a therapeutic target: further analysis of the mechanisms by which Nef activates AP-1 sites might lead to the design of new anti-HIV therapies.