Disruption of excitatory amino acid transporters in brains of SIV-infected rhesus macaques is associated with microglia activation.
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.
Meisner
Falko
F
Institute of Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
Neuen-Jacob
Eva
E
Sopper
Sieghart
S
Schmidt
Michaela
M
Schlammes
Serge
S
Scheller
Carsten
C
Vosswinkel
Daniel
D
Ter Meulen
Volker
V
Riederer
Peter
P
Koutsilieri
Eleni
E
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000821:virology; D004195:Disease Models, Animal; D018450:Disease Progression; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D050491:Glutamate Plasma Membrane Transport Proteins / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism / Q000821:virology; D008253:Macaca mulatta; D017628:Microglia / Q000502:physiology* / Q000821:virology; D021381:Protein Transport / Q000502:physiology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000378:metabolism* / Q000473:pathology*; D015302:Simian Immunodeficiency Virus; D018709:Statistics, Nonparametric
D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins