Human Immunodeficiency Virus Type 1 Nef: Adapting to Intracellular Trafficking Pathways

Abstract

SUMMARY The Nef protein of primate lentiviruses is a unique protein that has evolved in several ways to manipulate the biology of an infected cell to support viral replication, immune evasion, pathogenesis, and viral spread. Nef is a small (25- to 34-kDa), myristoylated protein that binds to a collection of cellular factors and acts as an adaptor to generate novel protein interactions to accomplish specific functions. Of the many biological activities attributed to Nef, the reduction of surface levels of the viral receptor (CD4) and antigen-presenting molecules (major histocompatibility complex class I) has been intensely examined; recent evidence demonstrates that Nef utilizes multiple, distinct pathways to affect these proteins. To accomplish this, Nef promotes the formation of multiprotein complexes, recruiting host adaptor proteins to commandeer intracellular vesicular trafficking routes. The altered trafficking of several other host molecules has also been reported, and an emerging theory suggests that Nef generates pleiotrophic effects in the secretory and endocytic pathways that reprogram intracellular protein trafficking and may ultimately provide an efficient platform for viral assembly. This review critically discusses some of the major findings regarding the impact of human immunodeficiency virus type 1 Nef on host protein transport and addresses some emerging directions in this area of human immunodeficiency virus biology.

HIV-1 Nef Triggers Macrophage Fusion in a p61Hck- and Protease-Dependent Manner

“…Among Nef functions, its ability to affect cell surface protein trafficking, including CD4 or MHC I molecules, has been well characterized (16). Nef also influences intracellular signaling pathways by physically interacting with host cell proteins, thus modifying their localizations and functions (for reviews, see Refs.…”

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

“…More specifically, it has been proposed that Nef could reorganize actin to ensure initial viral core movement. Association of Nef with viral cores (Kotov et al, 1999) and cellular proteins involved in actin cytoskeleton dynamics such as Vav and PAK (a member of the p21-activated kinase family) could account to the early movement of the viral cores through cortical actin and into microtubules (Roeth and Collins, 2006). Therefore, it has been proposed that this function of Nef could account to the increase in virus infectivity .…”

“…The effect of Nef is dependent on its myristoylation and SH3 domains. While Nef myristoylation is required for its membrane association, the proline-rich SH3-binding domain is involved in Nef association with Vav, DOCK2-ELMO1, Rac and the cellular kinase Pak2 (Roeth and Collins, 2006). First, Vav is activated by the interaction between its C-terminal SH3 domain and PxxP motif in Nef leading to Vav's downstream effectors activation, resulting in morphological changes, cytoskeleton rearrangements and the activation of the c-Jun Nterminal kinase (JNK)/stress-activated protein kinase (SAPK) cascade (Fackler et al, 1999).…”

Illustrating the machinery of life: Viruses

“…Vpu is important for viral release and is thought to form an ion channel through the membrane [20] (1vpu and 1pi7). Nef (negative factor) interacts with several cellular systems to increase the replication and pathogenicity of the virus and is bound to the membrane through an attached myristoyl lipid [21,22] (1qa4 and 1avv). The envelope also includes cellular proteins that are trapped during budding of the virus, including ICAM-1, HLA-II, and others [23].…”