Neurotoxicity of CSF from HIV-infected humans

Approximately 15-20% of individuals infected with the human immunodeficienc y virus will develop severe neurological disease. This may be due in part t o virus-induced release of a number of putative neurotoxins. However, there is little information to predict which individuals will progress to dement ia or the precise mechanisms that drive pathogenesis. In an effort to ident ify early markers of neurological disease progression we used an in vitro b ioassay with rat cortical neurons to test for the presence of toxins in CSF from 40 HIV-infected humans with mild, minimal or no neurological disease. A subset of HIV-infected individuals was found to have significant toxic a ctivity in CSF indicating that toxic factors may be circulating prior to th e development of dementia. The toxicity was concentration dependent and due to a factor with a molecular mass of less than 30 kDa. Only a small propor tion of the cell death appeared to be due to apoptosis. Neuronal toxicity w as associated with a gradual accumulation of intracellular calcium in a sub set of cortical neurons over a period of 1-2 h and in the absence of a sign ificant acute response. Individuals with both high Viral burden and high CS F toxicity were significantly more likely to have neurological symptoms. Th ese initial analyses indicate that toxic factors are present in the CSF of HIV-infected patients that could serve as useful markers of neurological di sease progression and provide insights into pathogenic mechanisms in vivo.