Content area
Abstract
A subset of Human Immunodeficiency Virus Type-1 (HIV-1) infected individuals experience a constellation of motor, cognitive, and psychiatric symptoms that are collectively called the Acquired Immunodeficiency Syndrome Dementia Complex (ADC). Experimental data have implicated glycoprotein 120 (gp120), an HIV-1 protein that facilitates viral entry into target cells, in neuronal cell death in ADC, but the molecular mechanism of its neurotoxic effect is unknown. Dysfunction of the nigro-striatal circuitry of the basal ganglia is integral to the neuropathology of ADC. Brain-derived neurotrophic factor (BDNF), a neurotrophic factor crucial for brain development and protection of dopaminergic nigro-striatal neurons against toxins and injury, may therefore confer neuroprotection against gp120-mediated neurotoxicity in the basal ganglia. Here, intrastriatal injection of gp120 was found to decrease trophic support and cause caspase-3 dependent neuronal apoptosis and dopaminergic dysfunction in the striatum and substantia nigra. Overexpression of BDNF by somatic gene transfer conferred protection against gp120-mediated neurotoxicity by a mechanism involving modulation of CXCR4, a chemokine receptor that is a co-receptor for gp120. These results raise the possibility that neuroprotection against gp120 by BDNF may in turn limit neurological complications associated with HIV-1 infection in the brain.
