fig1
Figure 1. Schematic illustration of EV-mediated signalling pathways that contribute to HAND in the setting of persistent HIV-1 viral proteins and opioid exposure. HIV-1 Tat stimulates astrocytes to release ADEVs enriched with pathogenic microRNAs and toxic cargo. EV-associated miR-9 is transferred to microglia, where it suppresses PTEN, promoting microglial migration and activation. Tat-induced ADEVs also deliver miR-7 to neurons, resulting in downregulation of NLGN2, impaired synaptic integrity, and neuronal dysfunction. HIV-1 Tat also activates microglia and the NLRP3 inflammasome, resulting in the release of MDEVs containing NLRP3. Transfer of these EVs to neurons amplifies neuroinflammation, induces synaptodendritic degeneration, and promotes neuronal cell death. BDEV-associated miR-21, released during lentiviral CNS infection, activates neuronal TLR7, triggering RIPK1-dependent necroptosis and further contributing to neurodegeneration. Opioid exposure further exacerbates EV-mediated neuropathology. Morphine stimulates astrocytes to release ADEVs enriched in miR-23a and miR-29b. Transfer of miR-23a to pericytes suppresses PTEN, activates the Akt signalling pathway, promotes pericyte migration and loss of vascular coverage, and increases blood-brain barrier permeability, facilitating peripheral monocyte infiltration into the CNS. EV-associated miR-29b suppresses neuronal PDGF-B, reducing neuronal viability and increasing susceptibility to injury. EV: Extracellular vesicle; HAND: HIV-associated neurocognitive disorders; ADEV: astrocyte-derived extracellular vesicle; miR-9: microRNA-9; PTEN: phosphatase and tensin homolog; miR-7: microRNA-7; NLGN2: neuroligin-2; MDEV: microglia-derived extracellular vesicle; NLRP3: NLR family pyrin domain containing 3; BDEV: brain-derived extracellular vesicle; miR-21: microRNA-21; TLR7: Toll-like receptor 7; RIPK1: receptor-interacting serine/threonine-protein kinase 1; miR-23a: microRNA-23a; Akt: protein kinase B; miR-29b: microRNA-29b; PDGF-B: platelet-derived growth factor B; CNS: central nervous system.
