Disruption of excitatory amino acid transporters in brains of SIV‐infected rhesus macaques is associated with microglia activation

Abstract

Glutamate‐mediated neurodysfunction in human immunodeficiency virus (HIV) infection has been primarily suggested by in vitro studies. The regulation of glutamatergic neurotransmission in inflammation is a complex interaction between activation of immune mediators and adaptive changes in the functional elements of the glutamatergic synapse. We have used simian immunodeficiency virus (SIV)‐infected macaques to answer the questions (i) whether perturbation of glutamate neurotransmission is evident during progression of immunodeficiency disease and (ii) what are the mechanisms underlying this impairment. Disease progression in SIV‐infected macaques both in the periphery and in the brain was documented by clinical and general pathological examination, plasma and brain viral RNA load, T‐cell analysis and brain histopathology. We report for the first time, disruption of excitatory amino acid transporters (EAATs), the cardinal glutamate clearing system, during SIV infection and a dramatic loss of EAATs associated with development of rapid acquired immunodeficiency syndrome (AIDS). EAATs impairment was correlated with activation status of microglia. Our data support the glutamate hypothesis for the development of HIV dementia and suggest that the pathogenetic mechanism for the neurodysfunction is the impairment of glutamate clearing which occurs in the stage of AIDS and which is associated with activated microglia.

Glutamate metabolism and HIV-associated neurocognitive disorders

“…Changes in brain metabolites have been detected shortly after infection and correlate with profound astrogliosis as well as viremia (Greco et al , 2004; Kim et al , 2005). To explore the changes in the environment of the glutamatergic synapses, the expression of the EAATs in the putamen of macaques infected with either neurotropic SIVmac251 or SIVmac239 was analyzed (Meisner et al , 2008). Macaques that progressed to AIDS exhibited a greater loss in EAAT-1 and EAAT-2 expression as compared to asymptomatic and control macaques (Meisner et al , 2008).…”

“…To explore the changes in the environment of the glutamatergic synapses, the expression of the EAATs in the putamen of macaques infected with either neurotropic SIVmac251 or SIVmac239 was analyzed (Meisner et al , 2008). Macaques that progressed to AIDS exhibited a greater loss in EAAT-1 and EAAT-2 expression as compared to asymptomatic and control macaques (Meisner et al , 2008). This progressive loss of EAAT-1 and EAAT-2 was associated with increased microglial activation and subsequent alteration of astrocytic function (Meisner et al , 2008).…”

“…Macaques that progressed to AIDS exhibited a greater loss in EAAT-1 and EAAT-2 expression as compared to asymptomatic and control macaques (Meisner et al , 2008). This progressive loss of EAAT-1 and EAAT-2 was associated with increased microglial activation and subsequent alteration of astrocytic function (Meisner et al , 2008). Astrocytes are the main cell type expressing these 2 transporters, thus under conditions that alter the expression of the transporters (i.e.…”

Complement and Microglia in the Neuropathogenesis of HIV Infection: Pro- and Anti-Inflammatory Aspects

“…However, diffuse activation of microglia is associated with decreased EAAT-2 expression as found in autopsy cases of HIV-infected individuals with or without HIVE [168]. We also demonstrated reduced EAAT-1 and EAAT-2 levels in the SIV/macaque model which correlate with microglia activation [216].…”

HIV patients treated with low-dose prednisolone exhibit lower immune activation than untreated patients

“…HIV patients with cognitive impairment or brain atrophy exhibit more elevated sCD14 levels than neurologically asymptomatic HIV-positive controls [40]. This link between monocyte activation and the neurological complications of HIV infection fits well into the overall picture in which microglia activation has been identified as a correlate with immunodeficiency virus-mediated neuropathy [41,42]. …”