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