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

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 glutamine 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 neuroprotective 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.

Evidence of reduced glutamate in the frontal lobe of HIV‐seropositive patients

“…Furthermore, Glu is not only an excitatory neurotransmitter in the central nervous system but also a metabolic substrate. The intracellular Glu pool has been implicated as a source of direct synthesis of glutathione in preclinical studies (45), in which, in the early stage of HIV infection, activation of glutathione synthesis, which requires Glu as substrate, has been reported (19,38). To our knowledge, this is the first report of measurements of uncontaminated Glu concentrations in the frontal WM and posterior cingulate gyrus brain regions of HIV-seropositive patients, using a reliable method to separate Glu from Gln (Fig.…”

Viruses and the brain: from inflammation to dementia

“…They express TNF-α, IL (interleukin)-1, IFN-α (interferon)-α and NOS [NO (nitric oxide) synthase], among other inflammatory mediators [52,53]. It should be noted, however, that recent work has shown that these cells may have neuroprotective properties, especially early in the infection [54,55], suggesting that the immune response has a desired effect initially and does not become damaging until the infection becomes chronic.…”

Glutamate‐mediated glial injury: Mechanisms and clinical importance

“…These transporters maintain basal levels of extracellular glutamate in the range of 1-2 lM and thus prevent overactivation of GluRs under physiological conditions. Interestingly, activated microglia and brain invading macrophages also express glutamate transporters after mechanical stimulation (van Landeghem et al, 2001) and HIV-induced CNS damage (reviewed by Gras et al, 2003) (Table 2).…”