Glutamate-mediated neurodysfunction plays a crucial role in the pathogenesis of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) encephalitis. 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. Our studies in simian immunodeficiency virus (SIV)-infected macaques disclosed 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) which was paralleled by activated microglia. N-methyl-D-aspartate (NMDA) receptor activation is involved in the pathogenetic cascades of neurodegenerative disorders including HIV dementia. The NMDA receptor antagonist memantine is being discussed as a potential adjunctive therapeutic drug for HIV dementia. Interestingly, in the SIV animal model, treatment with memantine during early asymptomatic stage prevented the onset of dopamine deficits in the brains of SIV-infected macaques and specifically up-regulated the brain-derived neurotrophic factor (BDNF). Our data support the glutamate hypothesis for the development of HIV dementia and suggest that the impairment of glutamate clearing plays an important role in the pathogenesis of HIV dementia and SIV encephalitis. Moreover, memantine might be a suitable drug for the treatment of HIV dementia due to its neuroprotective effect.