HIV-1 Nef Signaling in Intestinal Mucosa Epithelium Suggests the Existence of an Active Inter-kingdom Crosstalk Mediated by Exosomes

Abstract

The human intestinal mucosal surface represents the first defense against pathogens and regulates the immune response through the combination of epithelial cell (EC) functions and immunological factors. ECs act as sensors of luminal stimuli and interact with the immune cells through signal–transduction pathways, thus representing the first barrier that HIV-1 virus encounters during infection. In particular, the HIV-1 Nef protein plays a crucial role in viral invasion and replication. Nef is expressed early during viral infection and interacts with numerous cellular proteins as a scaffold/adaptor. Nef is localized primarily to cellular membranes and affects several signaling cascades in infected cells modulating the expression of cell surface receptors critical for HIV-1 infection and transmission, also accompanied by the production of specific cytokines and progressive depletion of CD4+ T cells. At the intestinal level, Nef contributes to affect the mucosal barrier by increasing epithelial permeability, that results in the translocation of microbial antigens and consequently in immune system activation. However, the pathological role of Nef in mucosal dysfunction has not been fully elucidated. Interestingly, Nef is secreted also within exosomes and contributes to regulate the intercellular communication exploiting the vesicular trafficking machinery of the host. This can be considered as a potential inter-kingdom communication pathway between virus and humans, where viral Nef contributes to modulate and post-transcriptionally regulate the host gene expression and immune response. In this mini-review we discuss the effects of HIV-1 Nef protein on intestinal epithelium and propose the existence of an inter-kingdom communication process mediated by exosomes.

Extracellular Vesicles in Viral Spread and Antiviral Response

“…EVs may also modulate retroviral pathogenesis [ 86 , 87 ]; HIV and simian immunodeficiency viruses modulate vesicle secretion through the Nef protein, which is secreted in exosomes and modifies intracellular trafficking pathways, enhancing viral infectivity and regulating host gene expression and immune responses [ 88 , 89 , 90 , 91 ]. In addition, TNFα release by cells upon incorporation of exosomes secreted by infected cells may reactivate latent HIV-1 [ 92 ].…”

The role of exosomal transport of viral agents in persistent HIV pathogenesis

“…The authors further showed that this disruption was due at least in part to a Nef-induced downregulation of zona occludin-1, also referred to as tight junction protein 1, which they hypothesized weakened the tight junctions between endothelial cells [107]. The effects of secreted Nef, exosomal and otherwise, on tight junction integrity has led to speculation that exosomes containing Nef may contribute to endothelial disruption in the gut as well, though there is not much evidentiary support for that hypothesis as of yet [108]. It is also of note that other HIV proteins such as Tat, Vpr, and gp120 also weaken the BBB by several mechanisms, such as downregulation and/or oxidative stress-induced phosphorylative dysregulation of tight junction proteins [109].…”

Prokaryotes Rule the World

“…Also, bacteria can sense various components of the immune system such as cytokines, apolipoprotein B (ApoB), Nox2, and antimicrobial peptides, modulating the host immune responses [92]. The possibility of interkingdom communication between Nef protein of HIV-1 virus and the host through exosomes has been recently reviewed, which extends the existence of QS other than in bacteria [94]. Likewise, QS can occur in animals and plants [92].…”