Human immunodeficiency virus protein Tat induces oligodendrocyte injury by enhancing outward K current conducted by K1.3.

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) channels induces cell apoptosis and Ols predominantly express K channel K1.3. It is our hypothesis that Tat injures Ols via activation of K1.3. To test this hypothesis, we studied the involvement of K1.3 in Tat-induced Ol/myelin injury both in vitro and ex vivo. Application of Tat to primary rat Ol cultures enhanced whole-cell K1.3 current recorded under voltage clamp configuration and confirmed by specific K1.3 antagonists Margatoxin (MgTx) and 5-(4-phenoxybutoxy) psoralen (PAP). The Tat enhancement of K1.3 current was associated with Tat-induced Ol apoptosis, which was blocked by MgTx and PAP or by siRNA knockdown of K1.3 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 K1.3 antagonists. Further studies revealed that Tat interacts with K1.3 as determined by protein pull-down of recombinant GST-Tat with K1.3 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 K1.3 in Tat- induced Ol/myelin injury, a potential mechanism for the pathogenesis of HIV-1-associated white matter damage.