Functions of the Lentiviral Accessory Protein Nef During the Distinct Steps of HIV and SIV Replication Cycle

Abstract

Human and Simian Immunodeficiency Viruses (HIV and SIV) are the etiological agents of the Acquired Immunodeficiency Syndrome (AIDS) in humans and the Simian AIDS (SAIDS) in macaques, respectively. HIVs and SIVs are members of the Retroviridae family, Lentivirus genera, and are considered complex retroviruses since its genome organization predicts the presence of at least 6 open reading frames (ORFs) in addition to the main Gag, Pol and Env ORFs present in the genomes of all retroviruses. These additional ORFs code for both regulatory (Tat and Rev) and accessory (Nef, Vif, Vpr, Vpu and Vpx) viral proteins and are all organized from the 5’ half of the genome in a way that overlap both with each other and with the Pol and Env ORFs and the non-coding 3’ Long Terminal Repeat (LTR) region (Figure 1). To ensure its expression and to achieve an optimal production of the viral progeny, complex mechanisms have evolved in these viruses that tightly control the expression of these ORFs during the viral replication cycle. The existence of such a number of viral proteins in addition to the viral structural (Gag and Env) and enzymatic (Pol) proteins allows the virus to explore new mechanisms to control the different steps of the replication cycle and to avoid the host cell defense. In this chapter we shall review the different steps of the HIV and SIV replication cycle with emphasis in the role taken by the viral accessory protein Nef, in both subverting the host cell machinery and influencing the function and activation of viral structural and enzymatic proteins in order to optimize viral progeny production as well as in evading the host cell defenses. Lentiviral accessory proteins Vif, Vpr, Vpu and Nef were classically regarded as nonessential for virus production and/or infectivity since laboratory adapted HIV strains lacking the expression of these proteins could still replicate to several levels (Adachi et al., 1991). Since then, several studies demonstrated the crucial importance of these proteins to the efficient replication, infectivity and spread of both HIV and SIV (Kirchhoff, 2010). Vif (Aguiar and Peterlin, 2008) and Vpu (Adachi et al., 1991) have now been acknowledged as crucial viral factors that counteract the host cell innate defense. Vif interacts and prompts the degradation of a family of cytidine deaminases DNA/RNA editing enzymes, known as Apoliprotein B mRNA-editing Enzymes (APOBECs), that otherwise would inhibit HIV and SIV replication by causing hypermutation of nascent