HIV-1-induced neuronal injury in the developing brain.
HIV-1 infection of the nervous system causes neuronal injury and death, resulting in cognitive, motor, and behavioral dysfunction in both adults and children. 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 particularly vulnerable to excitotoxic neuronal injury due to the active synaptogenesis and pruning that takes place at this age associated with over-expression of excitatory amino acid (EAA) receptors. HIV-1 infection of brain microglia and perivascular macrophages results in chronic inflammation manifest pathologically as diffuse microglial activation and reactive astrogliosis. Several inflammatory products of activated microglia, including tumor necrosis factor alpha (TNF-alpha) and platelet-activating factor (PAF) have been shown to act as neuronal toxins. This toxic effect can be antagonized by blocking NMDA (or AMPA) glutamate receptors, suggesting that (weak) excitotoxicity leads to oxidative stress, neuronal injury, and apoptosis. HIV-1 infection and chronic inflammation may also contribute disruption of the blood-brain barrier and could result in further entry into the CNS of toxic viral or cellular products or additional HIV-1-infected cells. We hypothesize that prolonged microglial activation during HIV-1 infection underlies the neuronal injury and impaired brain growth in affected infants. Further investigation of the interaction between HIV-1-infected/activated microglia and developing neurons seems warranted. The current understanding of HIV neuropathogenesis implies that therapeutic strategies should target the sustained immune activation in microglia, attempt to repair the integrity of the blood-brain barrier, and provide "neuroprotection" from excitotoxic neuronal injury.
Epstein
L G
LG
Department of Neurology, University of Rochester, New York, USA. L-epstein@nwu.edu
Gelbard
H A
HA
D000818:Animals; D001921:Brain / Q000254:growth & development* / Q000276:immunology / Q000473:pathology* / Q000821:virology; D015658:HIV Infections / Q000150:complications / Q000276:immunology / Q000473:pathology*; D015497:HIV-1 / Q000276:immunology / Q000472:pathogenicity*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D009474:Neurons / Q000276:immunology / Q000473:pathology* / Q000821:virology