| During the later stages of HIV-1 disease, a broad spectrum of behavioral, motor, and cognitive deficits occur as symptoms of HIV-1-associated dementia (HAD). These perturbations progress to impairments in memory and learning, and in severe cases, florid hallucinations, coma, and death. This disease is typically perpetrated by the egress of virally infected mononuclear phagocytes into brain. Such immune competent cells secrete a variety of pro-inflammatory molecules that cause neuronal damage by engaging specific receptors and affect cells indirectly by inciting inflammation, By implanting HIV-1 infected human monocyte-derived macrophages (MDM) into mice, we were able to induce HIV-1 encephalitis (HIVE), the histopathological correlate of HAD in severe combined immunodeficient (SCID) mice. We found that animals implanted with HIV-1 MDM (HIVE mice), showed reduced expression of microtubule associated protein 2 (MAP-2) in the CA1 region of hippocampus. Electrophysiology studies in hippocampal slices demonstrated that HIVE mice present deficits in synaptic plasticity and transmission. Furthermore, it was found that the N-methyl-D-aspartate (NMDA) antagonist memantine was able to ameliorate these deficits in HIVE SCID mice, revealed by both electrophysiology and histology. Lastly, in order to uncover potential proteins associated with these neuronal disturbances, hippocampal tissue from HIVE mice underwent protein profiling. Differences in protein species expression was found between groups. Specifically, proteins found in mice implanted with human MDM were absent or down-regulated in mice without MDM implantation or with MDM implantation and treated with memantine. Overall, these findings support the hypotheses that the presence of a few HIV-1 infected MDM in the brain can adversely affect neuronal function distant from the site of implantation, that HIV-1 neuronal dysfunction occurs in part through activation of the NMDA receptor, and that there exist differences in the protein profiles of hippocampal neurons subjected to HIV-1 MDM secretions. Notably, these findings also imply that memantine may be a useful potential therapeutic for the treatment of HIVE and HAD. |
