The HIV-1 Nef Protein Binds Argonaute-2 and Functions as a Viral Suppressor of RNA Interference

Abstract

The HIV-1 accessory protein Nef is an important virulence factor. It associates with cellular membranes and modulates the endocytic machinery and signaling pathways. Nef also increases the proliferation of multivesicular bodies (MVBs), which are sites for virus assembly and budding in macrophages. The RNA interference (RNAi) pathway proteins Ago2 and GW182 localize to MVBs, suggesting these to be sites for assembly and turnover of the miRNA-induced silencing complex (miRISC). While RNAi affects HIV replication, it is not clear if the virus encodes a suppressor activity to overcome this innate host response. Here we show that Nef colocalizes with MVBs and binds Ago2 through two highly conserved Glycine-Tryptophan (GW) motifs, mutations in which abolish Nef binding to Ago2 and reduce virus yield and infectivity. Nef also inhibits the slicing activity of Ago2 and disturbs the sorting of GW182 into exosomes resulting in the suppression of miRNA-induced silencing. Thus, besides its other activities, the HIV-1 Nef protein is also proposed to function as a viral suppressor of RNAi (VSR).

HIV‐1 Nef: Taking Control of Protein Trafficking

“…In contrast to the protective effects of exosomes from uninfected cells, exosomes from HIV‐1‐infected cells have been associated with enhancement of HIV‐1 pathogenesis, with distinct effects being attributed to Nef. Indeed, Nef has been shown to increase the cellular release of exosomes and other EVs and to alter the composition of these vesicles . Besides, Nef is itself secreted via EVs in vitro and in vivo , being present in blood plasma‐derived exosomes from infected individuals .…”

Potential Roles of Exosomal MicroRNAs as Diagnostic Biomarkers and Therapeutic Application in Alzheimer’s Disease

“…In addition to the above three selective modes, Guduric-Fuchs and his colleagues also revealed a possible involvement of miRISC in exosomal miRNA sorting mechanism, that is, (4) the miRNA-induced silencing complex- (miRISC-) related pathway: when AGO2 is knocked out, the main component of miRISC which prefers to bind to the 5′-end of miRNA reduces the number of privileged-transported miRNAs, such as miR-451 and miR-150, in HEK293T-derived exosomes [28]. Other findings have also confirmed the relationship and involvement of miRISC with exosomal miRNA sorting mechanism [29]. Specific sequences of miRNAs may guide their loading into exosomes, while some proteins may also contribute to the sorting of exosomal miRNAs.…”

An immunoregulatory role of dendritic cell-derived exosomes versus HIV-1 infection: take it easy but be warned

“…However, in HIV-1 infection, miRNAs are likely to play a minimal role in antiviral fight. HIV-1 protein Nef was observed to bind to Ago2, a key factor in miRNA biogenesis that leads to the inhibition of any RNA interference (61). Again, for example, the virus can stimulate overproduction of miR-29b and cause neural complications through exosome-dependent transport of this miRNA to astrocytes and subsequent down-regulation of expression of platelet-derived growth factor-B (PDGF-B), a growth factor of healing and amplification of neural cells (62).…”