Nearly 50% of individuals with long-term HIV infection are affected by the onset of progressive HIV-associated neurocognitive disorders (HAND). HIV infiltrates the central nervous system (CNS) early during primary infection where it establishes persistent infection in microglia (resident macrophages) and astrocytes that in turn release inflammatory cytokines, small neurotoxic mediators, and viral proteins. While the molecular mechanisms underlying pathology in HAND remain poorly understood, synaptodendritic damage has emerged as a hallmark of HIV infection of the CNS. Here, we report that the HIV viral envelope glycoprotein gp120 induces the formation of aberrant, rod-shaped cofilin-actin inclusions (rods) in cultured mouse hippocampal neurons via a signaling pathway common to other neurodegenerative stimuli including oligomeric, soluble amyloid-β and proinflammatory cytokines. Previous studies showed that synaptic function is impaired preferentially in the distal proximity of rods within dendrites. 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 active NADPH oxidase presumably through the formation of superoxide (O2-) and the expression of cellular prion protein (PrPC). These findings link gp120-mediated oxidative stress to the generation of rods, which may underlie early synaptic dysfunction observed in HAND.
The implementation of combination antiretroviral therapy (cART) as the primary means of treatment for HIV infection has achieved a dramatic decline in deaths attributed to AIDS and the reduced incidence of severe forms of HIV-associated neurocognitive disorders (HAND) in infected individuals. Despite these advances, milder forms of HAND persist and prevalence of these forms of neurocognitive impairment are rising with the aging population of HIV infected individuals. HIV enters the CNS early in the pathophysiology establishing persistent infection in resident macrophages and glial cells. These infected cells, in turn, secrete neurotoxic viral proteins, inflammatory cytokines, and small metabolites thought to contribute to neurodegenerative processes. The viral envelope protein gp120 has been identified as a potent neurotoxin affecting neurodegeneration via indirect and direct mechanisms involving interactions with chemokine co-receptors CCR5 and CXCR4. This short review focuses on gp120 neurotropism and associated mechanisms of neurotoxicity linked to chemokine receptors CCR5 and CXCR4 with a new perspective on plasma membrane lipid rafts as an active participant in gp120-mediated neurodegeneration underlying HIV induced CNS pathology.
While the implementation of combination antiretroviral therapy (cART) for the treatment of HIV‐1 infection has achieved a dramatic decline in deaths attributable to HIV/AIDS, it remains that upwards of 50% of individuals with long‐term HIV infection are affected by the onset of progressive neurological and cognitive complications referred to under the umbrella term HIV‐associated neurocognitive disorders (HAND). The viral envelope protein gp120 has been identified as a potent neurotoxin affecting neurodegeneration via mechanisms involving interactions with chemokine co‐receptors CCR5 and CXCR4. Early experiments have identified a role for dual‐tropic gp120 signaling through CCR5 and CXCR4 in the activation of a pathway common to oligomeric, soluble amyloid β linking oxidative stress to the formation of cofilin‐actin bundles (rods), which have been linked to synaptic dysfunction via sequestration of cofilin and the disruption of vesicular transport resulting from occlusion of neurites containing rods. Coalescence of lipid rafts paralleled by the activation of NADPH oxidase and a requirement for the cellular prion protein (PrPC) are central to this pathway. Here, we further characterize the role of the CXCR4 co‐receptor in gp120 induced lipid raft coalescence, reactive oxygen species (ROS) generation, and formation of rods in SH‐SY5Y human neuroblastoma cells expressing knocked‐down (siRNA) or overexpressed (lipofectamine‐based plasmid transfection) levels of CXCR4. Transgenic SH‐SY5Y cells were exposed to gp120IIIB (X4‐tropic) in a dose and time dependent manner. Cellular lipid raft coalescence, ROS generation, and the formation of rods were quantified and the contribution of CXCR4 specific gp120‐mediated signaling assessed. Here, we demonstrate that gp120IIIB signaling through CXCR4 induces potent raft coalescence, ROS and rod formation (p<0.05, one‐way ANOVA w/post‐hoc Dunnett's analysis, GraphPad Prism software). These results imply a potential link between HIV/co‐receptor interaction and the onset of early synaptic impairment mediated by the generation of cofilin‐actin rods.Support or Funding InformationINBRE Research reported in this publication was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103395. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the NIH. BLaST Research reported in this publication was supported by the National Institute Of General Medical Sciences of the National Institutes of Health under Award Numbers UL1GM118991, TL4GM118992, or RL5GM118990. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. UA is an AA/EO employer and educational institution and prohibits illegal discrimination against any individual: www.alaska.edu/titleIXcompliance/nondiscrimination.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.