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).
Highlights
The human immunodeficiency virus type 1 (HIV-1) expresses structural (Env, Gag), regulatory (Rev, Tat) and accessory (Nef, Vif, Vpr, Vpu) proteins, of which the last group of proteins are dispensable for virus infection and replication in vitro, but are essential for disease progression in the susceptible host [1]
Bodies that are sites for miRNA-mediated silencing [34] (Fig. 1C–iv). Another important component of miRNA-induced silencing complex (miRISC) is GW182, which is present in association with Ago2 in GW bodies on multivesicular bodies (MVBs) membranes [13,24]
In this study we show that HIV-1 Nef functions as a viral suppressor of RNA interference (VSR)
Summary
The human immunodeficiency virus type 1 (HIV-1) expresses structural (Env, Gag), regulatory (Rev, Tat) and accessory (Nef, Vif, Vpr, Vpu) proteins, of which the last group of proteins are dispensable for virus infection and replication in vitro, but are essential for disease progression in the susceptible host [1]. Nef is an ,27-kDa myristoylated protein that is expressed early during infection and functions as a multifunctional pathogenic factor [2]. It localizes to endosomal and plasma membranes and affects multiple cellular pathways, principally cellular activation, cell survival and apoptosis, and expression of cell surface receptors by virtue of its interaction with multiple cellular proteins [3,4]. The RNA interference (RNAi) pathway is an innate response that limits viral replication in plants, insects and higher animals [5,6,7]. Many recent reports suggest that the mammalian miRNA pathway functions in antiviral RNA-silencing to restrict the replication of infecting viruses [8]. Cellular miRNAs affect HIV-1 replication, either through direct targeting of viral RNAs [16] or through targeting of cellular RNAs necessary for viral replication [17]
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