HIV-1-induced neuronal injury in the developing brain

HIV-1 infection of the nervous system causes neuronal injury and death, res ulting in cognitive, motor, and behavioral dysfunction in both adults and c hildren. in infants a characteristic feature of HIV-1 infection is impaired brain growth resulting in secondary microcephaly with onset between 2 and 4 months of age. This post-natal period of brain development is particularl y vulnerable to excitotoxic neuronal injury due to the active synaptogenesi s and pruning that takes place at this age associated with over-expression of excitatory amino acid (EAA) receptors, HIV-1 infection of brain microgli a and perivascular macrophages results in chronic inflammation manifest pat hologically as diffuse microglial activation and reactive astrogliosis. Sev eral inflammatory products of activated microglia, including tumor necrosis factor alpha (TNF-alpha) and platelet-activating factor (PAF) have been sh own to act as neuronal toxins. This toxic effect can be antagonized by bloc king NMDA (or AMPA) glutamate receptors, suggesting that (weak) excitotoxic ity leads to oxidative stress, neuronal injury, and apoptosis. HIV-1 infect ion and chronic inflammation may also contribute disruption of the blood-br ain barrier and could result in further entry into the CNS of toxic viral o r cellular products or additional HIV-l-infected cells, We hypothesize that prolonged microglial activation during HIV-1 infection underlies the neuro nal injury and impaired brain growth in affected infants. Further investiga tion of the interaction between HIV-1-infected/activated microglia and deve loping neurons seems warranted. The current understanding of HIV neuropatho genesis implies that therapeutic strategies should target the sustained imm une activation hi microglia, attempt to repair the integrity of the blood-b rain barrier, and provide '"neuroprotection" from excitotoxic neuronal inju ry.