HIV-1 Tat Protein Increases Microglial Outward K+ Current and Resultant Neurotoxic Activity

Abstract

Microglia plays a crucial role in the pathogenesis of HIV-1-associated neurocognitive disorders. Increasing evidence indicates the voltage-gated potassium (Kv) channels are involved in the regulation of microglia function, prompting us to hypothesize Kv channels may also be involved in microglia-mediated neurotoxic activity in HIV-1-infected brain. To test this hypothesis, we investigated the involvement of Kv channels in the response of microglia to HIV-1 Tat protein. Treatment of rat microglia with HIV-1 Tat protein (200 ng/ml) resulted in pro-inflammatory microglial activation, as indicated by increases in TNF-α, IL-1β, reactive oxygen species, and nitric oxide, which were accompanied by enhanced outward K+ current and Kv1.3 channel expression. Suppression of microglial Kv1.3 channel activity, either with Kv1.3 channel blockers Margatoxin, 5-(4-Phenoxybutoxy)psoralen, or broad-spectrum K+ channel blocker 4-Aminopyridine, or by knockdown of Kv1.3 expression via transfection of microglia with Kv1.3 siRNA, was found to abrogate the neurotoxic activity of microglia resulting from HIV-1 Tat exposure. Furthermore, HIV-1 Tat-induced neuronal apoptosis was attenuated with the application of supernatant collected from K+ channel blocker-treated microglia. Lastly, the intracellular signaling pathways associated with Kv1.3 were investigated and enhancement of microglial Kv1.3 was found to correspond with an increase in Erk1/2 mitogen-activated protein kinase activation. These data suggest targeting microglial Kv1.3 channels may be a potential new avenue of therapy for inflammation-mediated neurological disorders.

Potassium Channel Kv1.3 Is Highly Expressed by Microglia in Human Alzheimer's Disease

“…For example, activated microglia after status epilepticus upregulate a potassium channel electro-physiologically identical to Kv1.3 [45]. HIV-Tat also induces Kv1.3 channel expression in microglia and blockade with 4-aminopyridine seems to abrogate neurotoxicity in-vitro [46]. Altered Kv1.3 channel regulation in microglia and blood-derived dendritic cells has also been observed in neuroinflammatory disease states such as radiation-induced brain injury and multiple sclerosis [24, 47].…”

HIV-1 Tat-Mediated Apoptosis in Human Blood-Retinal Barrier-Associated Cells

“…Therefore, cells were treated with Tat at a concentration of 0, 200, 400 or 600 ng/ml, respectively [21]. The HIV-1 Tat protein (PROSPEC, Israel) is a non-glycosylated polypeptide chain containing 86 amino acids.…”

Viral dependence on cellular ion channels – an emerging anti-viral target?

“…In neuronal tissue, the K v 1.3 outward-rectifier K + channel was shown to be modulated by the HIV-encoded Tat protein [34]. HIV-Tat was found to increase the surface expression of K v 1.3, which accompanied microglial activation and Tat-induced neurotoxicity [35]. Other HIV-neuronal ion channel interactions include HIV-gp120, which stimulates an outward K + conductance mediated by BK Ca and K v 2.1 channels [35,36].…”

“…Other HIV-neuronal ion channel interactions include HIV-gp120, which stimulates an outward K + conductance mediated by BK Ca and K v 2.1 channels [35,36]. As discussed, K v 2.1 activation leads to neuronal apoptosis and accordingly K v 2.1 inhibition could prevent gp120-mediated K + efflux and related apoptotic cell death [35].…”