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Abstract : Human immunodeficiency virus type 1 (HIV‐1) Tat induces neuronal apoptosis. To examine the mechanism(s) that contribute to this process, we studied Tat's effects on glycogen synthase kinase‐3β (GSK‐3β), an enzyme that has been implicated in the regulation of apoptosis. Addition of Tat to rat cerebellar granule neurons resulted in an increase in GSK‐3β activity, which was not associated with a change in protein expression and could be abolished by the addition of an inhibitor of GSK‐3β (lithium). Lithium also enhanced neuronal survival following exposure to Tat. Coprecipitation experiments revealed that Tat can associate with GSK‐3β, but direct addition of Tat to purified GSK‐3β had no effect on enzyme activity, suggesting that Tat's effects might be mediated indirectly. As the activation of platelet activating factor (PAF) receptors is critical for the induction of neuronal death by several candidate HIV …