The Role of Chemokine Co‐receptor CXCR4 in HIV‐1 gp120 Induced Synaptic Dysfunction
Authors: Smith Lisa K , McKee Heidi K , Kuhn Thomas B 
Published: June 2021

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 Information

INBRE 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.