Human immunodeficiency virus protein Tat induces oligodendrocyte injury by enhancing outward K+ current conducted by KV1.3

Abstract Brain white matter damage is frequently detected in patients infected with human immunodeficiency virus type 1 (HIV-1). White matter is composed of neuronal axons sheathed by oligodendrocytes (Ols), the myelin-forming cells in central nervous system. Ols are susceptible to HIV-1 viral trans-activator of transcription (Tat) and injury of Ols results in myelin sheath damage. It has been demonstrated that activation of voltage-gated K + (K V ) channels induces cell apoptosis and Ols predominantly express K + channel K V 1.3. It is our hypothesis that Tat injures Ols via activation of K V 1.3. To test this hypothesis, we studied the involvement of K V 1.3 in Tat-induced Ol/myelin injury both in vitro and ex vivo. Application of Tat to primary rat Ol cultures enhanced whole-cell K V 1.3 current recorded under voltage clamp configuration and confirmed by specific K V 1.3 antagonists Margatoxin (MgTx) and 5-(4-phenoxybutoxy) psoralen (PAP). The Tat enhancement of K V 1.3 current was associated with Tat-induced Ol apoptosis, which was blocked by MgTx and PAP or by siRNA knockdown of K V 1.3 gene. The Tat-induced Ol injury was validated in cultured rat brain slices, particularly in corpus callosum and striatum, that incubation of the slices with Tat resulted in myelin damage and reduction of myelin basic protein which were also blocked by aforementioned K V 1.3 antagonists. Further studies revealed that Tat interacts with K V 1.3 as determined by protein pull-down of recombinant GST-Tat with K V 1.3 expressed in rat brains and HEK293 cells. Such protein-protein interaction may alter channel protein phosphorylation, resultant channel activity and consequent Ol/myelin injury. Taken together, these results demonstrate an involvement of K V 1.3 in Tat- induced Ol/myelin injury, a potential mechanism for the pathogenesis of HIV-1-associated white matter damage.