GSK3-beta Inhibitors in Preventing HIV Neurodegeneration

Ian P. Everall, UC San Diego

HIV neurocognitive impairment (HNCI) is estimated to affect around 50% of HIV individuals. This frequency persists despite the introduction of highly active antiretroviral therapy (HAART). HAART does not appear to be effective in entering the brain, suppressing viral replication and ameliorating HIV associated neurodegeneration. As a result the development of brain directed adjunctive therapies are warranted. Previously, we have observed in vitro that fibroblast growth factor-1 (FGF1) and lithium prevent neurotoxicity associated with exposure to the HIV envelope protein gp120. Lithium is a known inhibitor of glycogen synthase kinase 3-beta (GSK3b) and we have demonstrated that the neuroprotective mechanism of FGF1 involves inhibition of GSK3b. Therefore inhibition of GSK3b presents a novel target for therapeutic development especially as stimulation of GSK3b is associated with apoptosis and in neurons GSK3b regulates synaptic and dendritic maintenance. Currently, specific inhibitors of GSK3b activity are becoming available for laboratory use and their efficacy in a range of neurodegenerative disorders are being investigated. In the context of our observation of HIV neurodegeneration, which underlies HNCI, in this proposal we wish to achieve two specific aims. Firstly, we will determine the optimal dose and duration of exposure of primary human neurons to two specific GSK3b inhibitors to effectively inhibit GSK3b activity without causing neurotoxicity. Secondly, we will use this GSK3b inhibitor dose and duration data to assess the whether the two inhibitors can effectively prevent HIV gp120 mediated neurodegeneration. Of relevance, GSK3b inhibitors are currently being assessed in animal models of neurodegenerative disorders including Alzheimer's disease. Positive data generated by thie IDEA funded proposal on the effect of inhibition of GSK3b on neuroprotection from the toxic effects of HIV gp120 the data will form the foundation to support future applications for extramural funding to translate these findings towards clinical practice.