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Abstract
Infection with human immunodeficiency virus-1 (HIV-1) within the brain has long been known to be associated with neurodegeneration and neurocognitive disorder (referred as HAND), a condition characterized in its early stages by declining cognitive function and behavioral disturbances. Mechanistically, the HIV-1 coat glycoprotein 120 (gp120) has been suggested to be a critical factor inducing apoptotic cell death in neurons via the activation of p38 mitogen-activated protein kinase (MAPK), upon chronic exposure to the virus. Here we show that acute exposure of neurons to HIV-1 gp120 elicits a homeostatic response, which provides protection against non-apoptotic cell death, involving the major somatodendritic voltage-gated K+ (Kv) channel Kv2.1 as the key mediator. The Kv2.1 channel has recently been shown to provide homeostatic control of neuronal excitability under conditions of seizures, ischemia and neuromodulation/neuroinflammation. Following acute exposure to gp120, cultured rat hippocampal neurons show rapid dephosphorylation of the Kv2.1 protein, which ultimately leads to changes in specific sub-cellular localization and voltage-dependent channel activation properties of Kv2.1. Such modifications in Kv2.1 are dependent on the activation of the chemokine co-receptors CCR5 and CXCR4, and subsequent activation of the protein phosphatase calcineurin. This leads to the overall suppression of neuronal excitability and provides neurons with a homeostatic protective mechanism. Specific blockade of calcineurin and Kv2.1 channel activity led to significant enhancement of non-apoptotic neuronal death upon acute gp120 treatment. These observations shed new light on the intrinsic homeostatic mechanisms of neuronal resilience during the acute stages of neuro-HIV infections.
Highlights
According to the United Nations Programme on human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS), approximately 34 million people Worldwide are infected with HIV [1]
Aside from the devastating immunological effects of the resultant AIDS, as many as 40% of HIV-positive patients suffer from varying degrees of neuroviral infection and subsequent HIV-associated neurodegeneration and neurocognitive disorder (HAND), which can lead to cognitive decline and diminished quality of life [2]
We have previously shown that rapid elevation of neuronal Ca2+ levels by increased excitatory activity, neuromodulatory and neuroinflammatory stimuli lead to the activation of calcineurin [8,23,24,29]
Summary
According to the United Nations Programme on human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS), approximately 34 million people Worldwide are infected with HIV [1]. It has been reported that the endogenous chemokine ligands for CXCR4, stromal cellderived factor 1-alpha (SDF-1α), and for CCR5, regulated on activation, normal T cell expressed and secreted (RANTES) elicit substantial [Ca2+]i in neurons [8,10,14], which subsequently activates the Ca2+/calmodulin-dependent protein phosphatase 2B or calcineurin [8,18] This leads to dephosphorylation of multiple proteins in mammalian brain neurons, including the principal voltage-gated K+ (Kv) channel Kv2.1 [8], which is the major constituent of total delayedrectifier K+ currents (IDR) [19,20,21]. This phenomenon has been shown to underlie homeostatic suppression of hyperexcitability in response to excitotoxic stimuli such as seizures and ischemia, as well as under neuromodulatory and neuroinflammatory conditions [21,28,29]
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