Browsing College of Natural Science and Mathematics (CNSM) by Subject "AIDS dementia complex"
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Role of neurotropism in HIV-1 gp120 induced oxidative stress and neurodegenerationAn estimated 50% of individuals with long-term HIV infection are affected by the onset of progressive neurological and cognitive complications referred to as HIV-associated neurocognitive disorders (HAND). While the molecular mechanisms underlying pathology in HAND remain poorly understood, synaptodendritic damage has emerged as a hallmark of HIV infection of the CNS. This damage is likely mediated by a combination of indirect mechanisms involving the release of inflammatory mediators and viral proteins from infected glial cells, and direct effects mediated by the interaction of neurotoxic viral proteins with neuronal receptors. The neurotoxic HIV envelope glycoprotein gp120 interacts with neuronal receptors CCR5 and CXCR4 to induce the coalescence of lipid raft domains into large, stable platforms-- a proposed mechanism for clustering components of receptor-activated signaling cascades. The interaction of proteins with lipid-raft localized receptors as a mechanism of regulating pathologic signaling has been observed in other neurodegenerative diseases, most notably in Alzheimer's disease, where amyloid- (Aß) oligomers interact with lipid raft-anchored cellular prion protein PrPC to activate a pathway leading to the formation of cofilin-actin rods-like inclusions (rods) in neuronal processes. Rods have been linked to synaptic dysfunction via sequestration of cofilin and the disruption of vesicular transport resulting from the occlusion of neurites in which they form. Given similarities in neuronal response to gp120 and Aß, we sought to assess the ability of gp120 to induce rods. Here, we report viral envelope protein gp120 induces the formation of cofilin-actin rods in E16 mouse hippocampal neurons via a signaling pathway common to oligomeric, soluble amyloid-ß and inflammatory cytokines. Our studies demonstrate gp120 binding to either chemokine co-receptor CCR5 or CXCR4 is capable of inducing rod formation and signaling through this pathway requires the NADPH oxidase-mediated formation of superoxide (O2-) and the expression of cellular prion protein (PrPC). These results link gp120-mediated oxidative stress formation to the generation rods in a previously undescribed mechanism of early synaptic dysfunction observed in HAND.