HIV-1 Nef: Hacker of the Host Cell

Abstract

Nef is a tiny (206-amino acid) myristoylated protein that expresses early in the viral replication cycle and has a significant role in viral replication and pathogenesis. Even though no significant enzymatic functions of Nef have been reported, it is well-known to have interaction with several host cellular proteins (e.g., Pak2, Vav and Rac) [3]. Experiments using mouse models and Rhesus macaques have proved the importance of Nef, as models infected with Nef-deleted mutants did not display the typical disease progression towards clinical AIDS. Nef alters cellular pathways by acting as a multifarious molecular adaptor protein, with multiple conformations. It is a manipulator of protein trafficking, signal transduction cascades and apoptotic pathways that are mediated by a symphony of protein interactions with host cell factors. It modulates components of the endocytic sorting and T-cell receptor signaling machineries, and also host adapter proteins like Vav, Pak-2, Rac, CDC42 and the DOCK2–ELMO1 complex, resulting in alteration of signal transduction pathways [4]. Nef also inhibits apoptosis by modulating p53- and ASK1-involved apoptotic pathways [5]. Nef removes CD4 from the cell surface, which may interfere with viral budding. It also binds to Gag–Pol and AIPI (a critical intermediate in the formation of multivesicular bodies), which contributes to the egress of viral particles from already-infected cells, such as via budding. Nef removes MHC-I from the cell surface, which makes it impossible for the cytotoxic T lymphocytes (CTLs) to recognize infected cells via peptides presented on MHC-I [6]. The downregulation of MHC-I decreases the efficiency of killing of HIV-1-infected cells by CTLs [7]. Nef expression in early viral life cycle stages contributes to the two most important attributes of HIV-1 infection; T-cell activation and the maintenance of a stable state of infection. Its absence may completely prevent the development of AIDS, as Nef expression is an important requisite for efficient HIV-1 replication in the infected host cells, which suggests that it is a valid target for antiretroviral activity.