The Role of Neurotropism in HIV‐1 gp120 Induced Oxidative Stress and Neurodegeneration
Authors: Smith Lisa , Walsh Keifer , Whittington Lindsey , Shaw Alisa , Minamide Laurie , Watson Katrina , Cartagena Gabriel , Bamburg James , Kuhn Thomas 
Published: November 2023

Human immunodeficiency virus 1 (HIV‐1) infection is linked to late onset neurological and cognitive dysfunctions, termed HIV associated neurocognitive disorders (HAND), despite the use of antiretroviral therapies. Each stage of the HIV‐1 life cycle (binding, fusion, and subsequent budding) critically depends on host‐cell lipid raft domains. Entry of HIV‐1 into neurons requires binding of the viral surface glycoprotein gp120 to CD4 receptors in lipid raft domains and subsequent conformational changes facilitate recruitment of the chemokine co‐receptors CCR5 or CXCR4. The preferential binding of gp120 to co‐receptors determines viral tropism, with R5 tropic strains binding CCR5, X4 tropic strains binding CXCR4, and dual tropic R5/X4 strains binding both receptors. Notably, X4 and dual‐tropic strains of HIV‐1 gp120 emerge later in infection and correspond with onset of neurological symptoms reminiscent of Alzheimer's disease (AD). Interestingly, binding of both dual‐tropic gp120MN and soluble, oligomeric amyloid β (Aβ) induces raft coalescence into membrane macrodomains. Exposure of human SH‐SY5Y neuroblastoma cells to 250, 500, and 750pg gp120MN over time (2.5, 5, and 7.5 hrs.) led to an increase in raft coalescence. Treatment with 750pg gp120MN for 2.5 hours lead to a significant increase in raft area/intensity ratio, (H=432.2, 5 df, n=9, p<0.0001), with significant increases (*p£0.05) detected for all doses at 5 and 7.5 hours. A signaling pathway common to gp120, Aβ, and several cytokines has been implicated in the production of reactive oxygen species (ROS) by neuronal NADPH oxidase 2 (NOX2) and the generation of rod‐like actin inclusions in primary hippocampal neurons. Hippocampal neurons exposed to1 ng/ml gp120MN provoked a rapid 22–25% increase in ROS production and a significant increase in the percentage of neurons with rods in a dose/time dependent manner (15.3±1.9 vs. 39.5±9.6 % neurons w/rods, control and 750pM gp120 respectively. p<0.05, n=3, 16hr incubation). Generation of rods was abolished by inhibiting NOX2, suggesting a causative role for NOX2‐mediated ROS activation in the formation of actin rods.To further explore the role of HIV‐1 neurotropism in neurodegeneration, we characterized the involvement of CCR5 and CXCR4 co‐receptors using R5 and X4 tropic gp120 (gp120CM and gp120LAV, respectively). Previously it was suggested that the tropic switch from R5 to X4 gp120 may trigger early manifestations of HAND through a more potent activation of the NOX2 mediated generation of ROS and actin rods. Preliminary results suggest that gp120LAV (X4‐tropic) stimulates increases in lipid raft coalescence as well as increased ROS generation in SH‐SY5Y neuroblastoma cells, and the generation of rod‐like actin inclusions in E18 rat hippocampal neurons.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). 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 (LKS).