gp120, the coat glycoprotein of HIV, can damage CNS neurons. This appears to mostly involve an indirect pathway in which gp120 infects microglia, triggering the release of cytokines and glutamatergic excitotoxins which then damage neurons. A well-characterized response of cells to insults is to mobilize the heat stress response, a defense that has a number of protective consequences. We tested the capacity of gp120, at a dose well-documented to be neurotoxic, to activate the heat shock response in cultures from cortex and hippocampus, two brain regions sensitive to the neurotoxic effects of gp120. We found that gp120 failed to induce expression of hsp70, hsp25 or hsp90 in cortical or hippocampal cultures, under conditions where induction can be demonstrated in response to other insults. The failure of gp120 to induce a heat shock response is significant because we subsequently demonstrated that such an induction would have been beneficial. Specifically, over expression of hsp70 with a herpes viral amplicon vector protected cultured hippocampal neurons from gp120 neurotoxicity.