Up-regulation of the Neuronal Nicotinic Receptor α7 by HIV Glycoprotein 120 POTENTIAL IMPLICATIONS FOR HIV-ASSOCIATED NEUROCOGNITIVE DISORDER

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 alpha 7 (alpha 7-nAChR). Our results show that gp120, through activation of the CXCR4 chemokine receptor, induces a functional up-regulation of alpha 7-nAChRs. Because alpha 7-nAChRs have a high permeability to Ca2+, 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 alpha-bungarotoxin. The in vitro data are supported by RT-PCR and Western blot analysis, confirming a remarkable up-regulation of the alpha 7-nAChR in gp120-transgenic mice brains. Specifically, alpha 7-nAChR up-regulation is observed in mouse striatum, a region severely affected in HIV+ patients. In summary, CXCR4 activation induces up-regulation of alpha 7-nAChR, causing cell death, suggesting that alpha 7-nAChR is a previously unrecognized contributor to the neurotoxicity associated with HIV infection.