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. 2006 Apr 5;13(2):211–222. doi: 10.1111/j.1750-3639.2003.tb00020.x

Regulated Expression of Sodium‐dependent Glutamate Transporters and Synthetase: a Neuroprotective Role for Activated Microglia and Macrophages in HIV Infection?

Gabriel Gras 1,✉, Fabrice Chrétien 1,2,3, Anne‐Valérie Vallat‐Decouvelaere 3, Gwenaelle Le Pavec 1, Fabrice Porcheray 1, Christophe Bossuet 1, Cathie Léone 1, Patricia Mialocq 1, Nathalie Dereuddre‐Bosquet 4, Pascal Clayette 4, Roger Le Grand 1, Christophe Créminon 5, Dominique Dormont 1, Anne‐Cécile Rimaniol 1, Françoise Gray 3
PMCID: PMC8095782  PMID: 12744474

Abstract

It is now widely accepted that neuronal damage in HIV infection results mainly from microglial activation and involves apoptosis, oxidative stress and glutamate‐mediated neurotoxicity. Glutamate toxicity acts via 2 distinct pathways: an excitotoxic one in which glutamate receptors are hyperactivated, and an oxidative one in which cystine uptake is inhibited, resulting in glutathione depletion and oxidative stress. A number of studies show that astrocytes normally take up glutamate, keeping extracellular glutamate concentration low in the brain and preventing excitotoxicity. This action is inhibited in HIV infection, probably due to the effects of inflammatory mediators and viral proteins. Other in vitro studies as well as in vivo experiments in rodents following mechanical stimulation, show that activated microglia and brain macrophages express high affinity glutamate transporters. These data have been confirmed in chronic inflammation of the brain, particularly in SIV infection, where activated microglia and brain macrophages also express glu‐tamine synthetase. Recent studies in humans with HIV infection show that activated microglia and brain macrophages express the glutamate transporter EAAT‐1 and that expression varies according to the disease stage. This suggests that, besides their recognized neurotoxic properties in HIV infection, these cells also have a neuroprotective function, and may partly make up for the inhibited astrocytic function, at least temporarily. This hypothesis might explain the discrepancy between microglial activation which occurs early in the disease, and neuronal apoptosis and neuronal loss which is a late event. In this review article, we discuss the possible neuro‐protective and neurotrophic roles of activated microglia and macrophages that may be generated by the expression of high affinity glutamate transporters and glutamine synthetase, 2 major effectors of glial glutamate metabolism, and the implications for HIV‐induced neuronal dysfunction, the underlying cause of HIV dementia.

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