Lipid Raft Coalescence Links HIV‐1 gp120 Induced Oxidative Stress to Neurodegeneration

Abstract

Host response to infection is a key determinant to disease pathogenesis. Hence, molecular understanding of host‐pathogen interactions provides a means of identifying novel therapeutic strategies in disease intervention. A number of pathogens, including the human immunodeficiency virus (HIV), utilize lipid rafts as their principal host entry portal. HIV1‐lipid raft interactions in the CNS are intimately linked to progressive neurodegeneration in a subset of infected individuals. Lipid rafts also play a critical role in other neurodegenerative diseases including Alzheimer disease. A signaling pathway common to amyloid β, cytokines, as well as HIV viral surface glycoprotein gp120 links oxidative stress and the formation of cofilin‐actin bundles (rods) to defects in synaptic function. Enhanced lipid raft coalescence mediated by the cellular prion protein (PrPC) and associated activation of NADPH oxidase are key to this pathway. Application of gp120 to SH‐SY5Y human neuroblastoma cells induced a time and dose‐dependent increase in lipid raft density reflected by a coalescence of lipid rafts into large macrodomains. Primary rat hippocampal neurons exposed to gp120 responded with a dose‐dependent formation of rods and increased lipid raft density. A rapid gp120‐induced production of reactive oxygen species (ROS) in hippocampal neurons was observed with the ROS‐sensitive fluorescence indicator DCF. NADPH oxidase activation in response to gp120 was causal to the formation of rods in hippocampal neurons. Blocking NADPH oxidase using either pharmacological inhibitors or by overexpressing dominant negative p22phox (a small membrane subunit of NOX) negated gp120‐mediated rod formation. More recent studies have identified a number of natural products that potently reduce viral infectivity. We demonstrate that a non‐polar fraction obtain from crude extracts of Alaskan wild bog blueberries (Vaccinium uliginosum) disrupt lipid raft coalescence in neurons exposed to neurotoxic stresses including gp120 and significantly decrease rod formation. In this scenario, lipid rafts serve as a signaling platform to progressive neurodegeneration associated with viral (AIDS dementia) as well as chronic degenerative CNS disorders. Natural products with the capability of modulating neurotoxic lipid raft signaling pathways could provide a novel approach to blunt progression of neurodegenerative processes.Support or Funding InformationSupported in part by NIH grants AG044812, AG049668, Camille & Henry Dreyfus Sr. Scientist Mentor Award, and CSU Core Infrastructure Grant Microscope Imaging (JRB), and P20GM103395 and the Alzheimer's Resources of Alaska (TBK)