Chemokine co-receptor CCR5/CXCR4-dependent modulation of Kv2.1 channel confers acute neuroprotection to HIV-1 glycoprotein gp120 exposure

PLoS One. 2013 Sep 24;8(9):e76698. doi: 10.1371/journal.pone.0076698. eCollection 2013.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Calcineurin / metabolism
  • Calcium / metabolism
  • Female
  • HIV Envelope Protein gp120 / pharmacology*
  • HIV-1*
  • Hippocampus / cytology*
  • Intracellular Space / drug effects
  • Intracellular Space / metabolism
  • Male
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Phosphorylation / drug effects
  • Protein Transport / drug effects
  • Rats
  • Receptors, CCR5 / metabolism*
  • Receptors, CXCR4 / metabolism*
  • Shab Potassium Channels / metabolism*
  • Signal Transduction / drug effects


  • HIV Envelope Protein gp120
  • Receptors, CCR5
  • Receptors, CXCR4
  • Shab Potassium Channels
  • gp120 protein, Human immunodeficiency virus 1
  • Calcineurin
  • Calcium