BENZODIAZEPINES, GLIA, AND HIV-1 NEUROPATHOGENESIS

Although the precise mechanisms whereby HIV-1 infection induces neurod egeneration have yet to be determined, a great deal of evidence has in criminated glial cells and the production of proinflammatory mediators in this pathologic process. For this reason, ideal therapeutic agents for the treatment of AIDS dementia would attenuate HIV-1 neuropathoge nesis through both direct inhibition of viral expression and suppressi on of brain cell-produced immune mediators. Benzodiazepines (BDZs), su ch as Valium, are extensively prescribed drugs for anxiety disorders, which readily cross the blood-brain barrier and have demonstrated immu nomodulatory properties. BDZs bind to primary human microglial cells, the principal site of HIV-1 replication in the brain, and inhibit lipo polysaccharide (LPS) induced tumour necrosis factor (TNF-alpha) produc tion by these cells in a concentration-dependent manner. Treatment of HIV-1-infected primary human microglial, as well as mixed glial/neuron al, cell cultures with BDZs inhibits the expression of HIV-1 p24 antig en. BDZ-induced inhibition of HIV-1 expression in chronically infected promonocytic (U1) cells has been found to be associated with decrease d activation of the nuclear transcription factor kappa B (NF-kappa-B). Because HIV-1 expression is critically dependent on the cellular tran scription machinery, inhibition of the activation of transcription fac tors, which participate in both HIV-1 expression and the production of neurotoxic immune mediators, by BDZ analog may provide new therapeuti c options for AIDS dementia.