Up-regulation of the Neuronal Nicotinic Receptor α7 by HIV Glycoprotein 120: Potential Implications for HIV-associated Neurocognitive Disorder

J Biol Chem. 2012 Jan 27;287(5):3079-86. doi: 10.1074/jbc.M111.262543. Epub 2011 Nov 14.

Abstract

Approximately 30-50% of the >30 million HIV-infected subjects develop neurological complications ranging from mild symptoms to dementia. HIV does not infect neurons, and the molecular mechanisms behind HIV-associated neurocognitive decline are not understood. There are several hypotheses to explain the development of dementia in HIV(+) individuals, including neuroinflammation mediated by infected microglia and neuronal toxicity by HIV proteins. A key protein associated with the neurological complications of HIV, gp120, forms part of the viral envelope and can be found in the CSF of infected individuals. HIV-1-gp120 interacts with several receptors including CD4, CCR5, CXCR4, and nicotinic acetylcholine receptors (nAChRs). However, the role of nAChRs in HIV-associated neurocognitive disorder has not been investigated. We studied the effects of gp120(IIIB) on the expression and function of the nicotinic receptor α7 (α7-nAChR). Our results show that gp120, through activation of the CXCR4 chemokine receptor, induces a functional up-regulation of α7-nAChRs. Because α7-nAChRs have a high permeability to Ca(2+), we performed TUNEL staining to investigate the effects of receptor up-regulation on cell viability. Our data revealed an increase in cell death, which was blocked by the selective antagonist α-bungarotoxin. The in vitro data are supported by RT-PCR and Western blot analysis, confirming a remarkable up-regulation of the α7-nAChR in gp120-transgenic mice brains. Specifically, α7-nAChR up-regulation is observed in mouse striatum, a region severely affected in HIV(+) patients. In summary, CXCR4 activation induces up-regulation of α7-nAChR, causing cell death, suggesting that α7-nAChR is a previously unrecognized contributor to the neurotoxicity associated with HIV infection.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • AIDS Dementia Complex / genetics
  • AIDS Dementia Complex / metabolism*
  • Animals
  • Bungarotoxins / pharmacology
  • Cell Death / genetics
  • Corpus Striatum / metabolism*
  • Corpus Striatum / virology
  • HIV Envelope Protein gp120 / genetics
  • HIV Envelope Protein gp120 / metabolism*
  • HIV-1 / genetics
  • HIV-1 / metabolism*
  • Humans
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Receptors, CXCR4 / genetics
  • Receptors, CXCR4 / metabolism*
  • Receptors, Nicotinic / genetics
  • Receptors, Nicotinic / metabolism*
  • Up-Regulation / drug effects
  • Up-Regulation / genetics
  • alpha7 Nicotinic Acetylcholine Receptor

Substances

  • Bungarotoxins
  • CXCR4 protein, mouse
  • Chrna7 protein, human
  • Chrna7 protein, mouse
  • HIV Envelope Protein gp120
  • Nerve Tissue Proteins
  • Receptors, CXCR4
  • Receptors, Nicotinic
  • alpha7 Nicotinic Acetylcholine Receptor
  • gp120 protein, Human immunodeficiency virus 1