Extracellular vesicles carrying HIV-1 Nef induce long-term hyperreactivity of myeloid cells

Neuro‐HIV—New insights into pathogenesis and emerging therapeutic targets

“…Recent findings from our group demonstrated that Nef EVs can induce immune training in monocytes and myeloid progenitor cells by a mechanism dependent on stimulation of glycolysis and changes in cholesterol homeostasis and lipid rafts, 128 resembling the mechanism described for β‐glucan 129 (Figure 3). Similarity between the trained immunity mechanisms induced by β‐glucan and Nef EVs is supported by their sensitivity to inhibitors of cholesterol biosynthesis and IGF1R signaling, stimulation of glycolysis, and activation of pro‐inflammatory genes via epigenetic modifications 128,129 . Intermediates of glycolysis, fumarate, and acetyl‐coenzyme A (Ac‐CoA) inhibit KDM5 histone demethylase and stimulate histone acetyltransferase, respectively, modifying the H3 histone to a transcriptionally active conformation, 129 which underlies overresponsiveness of Nef‐treated cells to inflammatory stimuli 128 .…”

“…Ac‐CoA also stimulates cholesterol biosynthesis, a side product of which, mevalonate, is secreted and interacts with IGF1R, initiating a signaling cascade that further stimulates glycolysis and cholesterol synthesis, enhancing epigenetic modifications and expansion of lipid rafts, where IGF1R is localized (Figure 3). Interestingly, epigenetic changes appear to suppress the expression of ABCA1 in Nef EVs‐treated cells, the effect that was not described for β‐glucan and which may further enhance ABCA1 inhibition induced by Nef EVs 128 . This concept is yet to be tested in brain cells, but if confirmed, this finding opens a possibility that chronic neuroinflammation may be maintained in HIV‐infected individuals even when all HIV‐specific factors are eliminated 130 …”

“…Similarity between the trained immunity mechanisms induced by β-glucan and Nef EVs is supported by their sensitivity to inhibitors of cholesterol biosynthesis and IGF1R signaling, stimulation of glycolysis, and activation of pro-inflammatory genes via epigenetic modifications. 128,129 Intermediates of glycolysis, fumarate, and acetyl-coenzyme A (Ac-CoA) inhibit KDM5 histone demethylase and stimulate histone acetyltransferase, respectively, modifying the H3 histone to a transcriptionally active conformation, 129 which underlies overresponsiveness of Nef-treated cells to inflammatory stimuli. 128 Ac-CoA also stimulates cholesterol biosynthesis, a side product of which, mevalonate, is secreted and interacts with IGF1R, initiating a signaling cascade that further stimulates glycolysis and cholesterol synthesis, enhancing epigenetic modifications and expansion of lipid rafts, where IGF1R is localized (Figure 3).…”

Training vs. Tolerance: The Yin/Yang of the Innate Immune System

“…Furthermore, our group demonstrated that gut microbiota cell-derived nano-sized biovesicles, known as extracellular vesicles (EVs), drive the induction of innate memory in murine bone-marrow neutrophils in a TLR2-dependent manner in vitro [ 115 ]. Similarly, the role of extracellular vesicles from HIV-infected humans maintaining persistent chronic inflammatory responses (phenomenon of trained immunity) of myeloid cells, associated with increased morbidities against secondary infections, has been described by Dubrovsky et al [ 116 ]. Although there are still many issues to be clarified, these studies nonetheless shed some encouraging light to the role of microbiota or bilipid-enclosed envelopes, such as EVs, encouraging trained effects in innate immune cells.…”

A Patching and Coding Lipid Raft-Localized Universal Imaging Platform

“…Cell membranes are composed of lipids and proteins and characterized by horizontal heterogeneity. , In particular, there are microdomains of specific lipids (e.g., cholesterol, saturated sphingolipids) and proteins (e.g., glycosylphosphatidylinositol (GPI)-anchored proteins) assembled in a tightly ordered manner in the cell membrane, called lipid rafts. , These microdomains can selectively recruit specific proteins such as mucin 1 (MUC1), tyrosine kinase, , and epidermal growth factor receptor (EGFR) − to trigger signal transduction pathways by aggregating signaling molecules such as membrane receptors or inducing structural modifications of specific proteins . These processes can mediate a variety of cellular functions, including cellular endocytosis, , cell membrane sorting, , host–pathogen interactions, , and immune signaling. − The recruitment of biomolecules to lipid rafts is regulated by several factors, including glycosylation. − McEver et al found that O -glycosylation and terminal sialylation were important for the targeting of P-selectin glycoprotein ligand-1, CD43, and CD44 to lipid rafts . Johnson et al reported that decreased N -glycosylation on neural cell adhesion molecule L1 (L1CAM) in the brain of CWH53 mutant mice reduced the proportion of L1CAM in lipid rafts, leading to the development of hydrocephalus …”