Voltage-gated K+ Channels and HIV-1-induced Neural Injury: Implications for Pathogenesis of HIV-1-associated Neurocognitive Disorders

Human immunodeficiency virus-1 (HIV-1)-associated neurocognitive disorder (HAND) is a subcortical disease involving neuronal loss and myelin damage. Myelin is deposited by oligodendrocytes through a complex process including oligodendrocyte progenitor cell (OPC) proliferation and maturation. Oligodendrocytes/OPCs are susceptible to viral proteins such as Tat and that myelin damage is associated with oligodendrocyte number decrease. It has been shown that activation of voltage-gated K+ (KV) channels mediates apoptosis in various cell types. KV1.3 is the most predominant KV channel expressed in OPCs/oligodendrocytes and potentially involved in OPC developmental regulation. We studied the involvement of KV1.3 in Tat-induced OPC/oligodendrocyte injury and OPC maturation deficit. Tat increased KV1.3 currents in cultured OPCs and oligodendrocytes may through direct interaction and interrupting channel phosphorylating regulation, leading to OPC maturation retardation and OPC/oligodendrocyte apoptosis. Tat-caused myelin injury was validated in corpus callosum and striatum of cultured rat brain slices. These effects were prevented by KV1.3 antagonists or KV1.3-siRNA knockdown. Gelsolin (GSN), an actin-binding protein best-known for its modulation of cell motility and secretion. Neurons appear to be a major source of GSN in CNS and GSN-null neurons have enhanced cell death. The GSN level is decreased in CSF of HIV-1-infected individuals. Studies have demonstrated that enhancement of KV currents results in neuronal apoptosis. To understand how the decreased level of GSN causes neuronal injury in HAND, we studied the effects of GSN on HIV-1 glycoprotein 120 (gp120)-activated outward K+ currents in primary rat cortical neuronal cultures. Gp120 enhanced outward K+ and resulted in neuronal apoptosis. GSN suppressed the gp120-induced outward K+ current increase and reduced vulnerability to gp120-induced neuronal apoptosis. The GSN-mediated suppression of gp120 enhancement of neuronal outward K+ current was blocked by KV2.1 inhibitor. In parallel, gp120 up-regulated KV2.1 channel expression, which was also blocked by GSN. Taken together, my thesis research demonstrates that Tat induces myelin damage by KV1.3-mediated OPC/oligodendrocyte injury and maturation defects, which may have implications for the pathogenesis of HAND. GSN protects neurons from gp120-associated changes by suppression of gp120-induced enhancement of KV2.1 K+ currents, which may reflect a neuroprotective role of GSN in HIV-1-infected brain