HIV‐1 Nef: Taking Control of Protein Trafficking

Abstract

The Nef protein of the human immunodeficiency virus is a crucial determinant of viral pathogenesis and disease progression. Nef is abundantly expressed early in infection and is thought to optimize the cellular environment for viral replication. Nef controls expression levels of various cell surface molecules that play important roles in immunity and virus life cycle, by directly interfering with the itinerary of these proteins within the endocytic and late secretory pathways. To exert these functions, Nef physically interacts with host proteins that regulate protein trafficking. In recent years, considerable progress was made in identifying host-cell-interacting partners for Nef, and the molecular machinery used by Nef to interfere with protein trafficking has started to be unraveled.Here, we briefly review the knowledge gained and discuss new findings regarding the mechanisms by which Nef modifies the intracellular trafficking pathways to prevent antigen presentation, facilitate viral particle release and enhance the infectivity of HIV-1 virions.

CD4 downregulation by the HIV-1 protein Nef reveals distinct roles for the γ1 and γ2 subunits of the AP-1 complex in protein trafficking

“…Our results also provide evidence that γ2 is a subunit of a new AP-1 variant, which functions in an endocytic pathway leading to late endosomes and lysosomes, and is functionally distinct from the canonical AP-1 complex containing the γ1 subunit. Because Nef plays a decisive role in HIV-1 pathogenesis, through the downregulation of host surface proteins (Pereira and daSilva, 2016;Sugden et al, 2016), it is important to test the role of γ2 in the downregulation of other Nef targets.…”

“…The first function ascribed to Nef was the ability to dramatically reduce cell surface levels of CD4 (Garcia and Miller, 1991;Guy et al, 1987; reviewed by Pereira and daSilva, 2016). Nef-mediated downregulation of CD4 is important to counteract the detrimental effects of high CD4 expression in HIV-infected cells, such as to prevent superinfection (Benson et al, 1993) and to facilitate the release of viral progeny (Cortés et al, 2002;Lama et al, 1999).…”

Unusual Fusion Proteins of HIV-1

“…Furthermore, viral proteins are often multifunctional and exert a multitude of immune evasion activities. The paragon of such a multitasking or moonlighting protein is HIV-1 Nef, which has been described to downmodulate a variety of surface receptors including CD4, MHC class I, CD28, and CXCR4, counteracts the host restriction factors SERINC3/5, and upregulates the invariant chain/CD74 to suppress antigen presentation (Pereira and daSilva, 2016). Finally, viral genomes are often very compact, containing overlapping genes that encode for bi- and multi-cistronic mRNAs.…”

HIV-1 Nef promotes migration and chemokine synthesis of human basophils and mast cells through the interaction with CXCR4

“…For example, Nef upregulates the surface expression of Tumor Necrosis Factor (TNF) and immature major histocompatibility complex class II (MHC-II). In contrast, Nef downregulates the surface expression of several other proteins including CD4, MHC-I, CD3, CD8, CD28, CXCR4, CCR5, CCR3, CD1, CD80/CD86, CTLA-4, mature (antigenic peptide-loaded) MHC-II [6]. Nef-mediated downregulation of MHC-I molecules, benefits the virus by interfering with the recognition and destruction of infected cells by cytotoxic T-cells [6].…”

“…In contrast, Nef downregulates the surface expression of several other proteins including CD4, MHC-I, CD3, CD8, CD28, CXCR4, CCR5, CCR3, CD1, CD80/CD86, CTLA-4, mature (antigenic peptide-loaded) MHC-II [6]. Nef-mediated downregulation of MHC-I molecules, benefits the virus by interfering with the recognition and destruction of infected cells by cytotoxic T-cells [6]. Besides its well-studied effects on intracellular signaling, Nef also acts through its secretion in exosomes nanovesicles.…”