HIV gp120‐induced neuroinflammation potentiates NMDA receptors to overcome basal suppression of inhibitory synapses by p38 MAPK

Abstract

HIV-associated neurocognitive disorder affects about half of HIV-infected patients. HIV impairs neuronal function through indirect mechanisms mainly mediated by inflammatory cytokines and neurotoxic viral proteins, such as the envelope protein gp120. HIV gp120 elicits a neuroinflammatory response that potentiates NMDA receptor function and induces the loss of excitatory synapses. How gp120 influences neuronal inhibition remains unknown. In this study, we expressed a green fluorescent protein (GFP)-tagged recombinant antibody-like protein that binds to the post-synaptic scaffolding protein gephyrin to label inhibitory synapses in living neurons. Treatment with 600 pM gp120 for 24 h increased the number of labeled inhibitory synapses. HIV gp120 evoked the release of interleukin-1b (IL-1b) from microglia to activate IL-1 receptors on neurons. Subsequent activation of the tyrosine kinase Src and GluN2A-containing NMDA receptors increased the number of inhibitory synapses via a process that required protein synthesis. In na€ ıve cultures, inhibition of neuronal p38 mitogen-activated protein kinase (p38 MAPK) increased the number of inhibitory synapses suggesting that p38 MAPK produces a basal suppression of inhibitory synapses that is overcome in the presence of gp120. Direct activation of a mutant form of p38 MAPK expressed in neurons mimicked basal suppression of inhibitory synapses. This study shows for the first time that gp120-induced neuroinflammation increases the number of inhibitory synapses and that this increase overcomes a basal suppression of synaptic inhibition. Increased inhibition may be an adaptive mechanism enabling neurons to counteract excess excitatory input in order to maintain network homeostasis.

Modeling HIV-1 neuropathogenesis using three-dimensional human brain organoids (hBORGs) with HIV-1 infected microglia

“…However, the less severe forms of disease, such as asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorder (MND), currently represent much more common forms of cognitive impairment, and post-mortem tissues do not allow the study of early stages of infection and disease progression. Post-mortem evaluations have been further supported by observations in the simian immunodeficiency virus (SIV)-infected non-human primates 18 , 19 and in vitro experimental studies utilizing two-dimensional (2D) tissue cultures models 20 – 24 . However, these approaches do not reflect the unique and dynamic features of the human brain physiology and inter-individual differences, notably those including the interaction with a human-specific virus as HIV-1.…”

“…experimental studies utilizing two-dimensional (2D) tissue cultures models [20][21][22][23][24] . However, these approaches do not reflect the unique and dynamic features of the human brain physiology and inter-individual differences, notably those including the interaction with a human-specific virus as HIV-1.…”

Effects of Antimalarial Drugs on Neuroinflammation-Potential Use for Treatment of COVID-19-Related Neurologic Complications

“…The ability of COVID-19 to produce a cytokine storm and inflammation might be at the centre of the pathogenicity of the virus, yet little is known about the component(s) of SARS-CoV-2 that is pro-inflammatory. In the case of HIV, it is the gp120 protein that has been found to be pro-inflammatory in neurons [ 22 ]. Research is urgently needed to identify the pro-inflammatory component(s) of SARS-CoV-2.…”

HIV-1 gp120 impairs spatial memory through CREB

“…HIV-1 gp120 is released from HIV-infected cells and can cause neuronal dysfunction (6). gp120 was reported to be toxic to neurons through activation of the NMDA receptor, causing an increase in Ca 2+ influx, activating the oxidative stress (OS) pathway, and allowing the release of toxic lipids from membranes (7). gp120 protein was also shown to alter mitochondrial functions (8) and axonal transport (9) causing neuronal deregulation.…”