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Up-regulation of the Neuronal Nicotinic Receptor α7 by HIV Glycoprotein 120

Open AccessPublished:November 14, 2011DOI:https://doi.org/10.1074/jbc.M111.262543
      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 gp120IIIB 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 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 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.

      Introduction

      More than 30 million people are infected with HIV worldwide (

      UNAIDS/WHO (2008) Report on Global AIDS Epidemic

      ). In addition to the health problems caused by immunosuppression, HIV infection causes HIV-associated neurocognitive disorder (HAND),
      The abbreviations used are: HAND
      HIV-associated neurocognitive disorder
      α-bgtx
      α-bungarotoxin
      ACh
      acetylcholine
      Egr-1
      early growth response gene 1
      gp
      glycoprotein
      HAART
      highly active antiretroviral therapy
      nAChR
      nicotinic ACh receptor
      pF
      pico-Farad
      SDF
      stromal cell-derived growth factor.
      a neurodegenerative disease that leads to severe cognitive, motor, and behavioral disturbances. Before the introduction of highly active antiretroviral therapy (HAART), 30–50% of HIV-infected patients developed HAND; after the incorporation of HAART as part of HIV treatment, the incidence decreased to ∼10% (
      • Tozzi V.
      • Balestra P.
      • Bellagama R.
      • Corpolongo A.
      • Salvatori M.F.
      • Visco-Comandini U.
      • Vlassi C.
      • Giulianelli M.
      • Galgani S.
      • Antinori A.
      • Narciso P.
      ,
      • Sacktor N.
      • Lyles R.H.
      • Skolasky R.
      • Kleeberger C.
      • Selnes O.A.
      • Miller E.N.
      • Becker J.T.
      • Cohen B.
      • McArthur J.C.
      ,
      • Njamnshi A.K.
      • Bissek A.C.
      • Ongolo-Zogo P.
      • Tabah E.N.
      • Lekoubou A.Z.
      • Yepnjio F.N.
      • Fonsah J.Y.
      • Kuate C.T.
      • Angwafor S.A.
      • Dema F.
      • Njamnshi D.M.
      • Kouanfack C.
      • Djientcheu Vde P.
      • Muna W.F.
      • Kanmogne G.D.
      ,
      • Sacktor N.
      ). Nevertheless, in association with the existence of HAART treatment, which prolongs the life of HIV-infected individuals, there has been an increase to ∼30% in the number of individuals who develop a milder form of neurocognitive dysfunction known as minor cognitive-motor disorder, which is characterized by neurological deficits that do not interfere with everyday functioning (
      • Wong M.H.
      • Robertson K.
      • Nakasujja N.
      • Skolasky R.
      • Musisi S.
      • Katabira E.
      • McArthur J.C.
      • Ronald A.
      • Sacktor N.
      ). Therefore, despite the reduction in HAND incidence, its prevalence is expected to increase due the improved care of HIV-infected patients. When evaluating the alterations in the incidence of HAND as a result of HAART, it is important to consider that of the ∼30 million HIV-infected individuals worldwide, only 2 million have access to HAART (

      UNAIDS/WHO (2008) Report on Global AIDS Epidemic

      ). In addition, HIV infection continues to be the most common cause of dementia in young adults in the United States (
      • Kaul M.
      ,
      • Ghafouri M.
      • Amini S.
      • Khalili K.
      • Sawaya B.E.
      ). This suggests that HAND will continue to be an important health care problem in the United States and worldwide.
      The presence of neurological symptoms in HIV-infected patients is an interesting finding, considering that HIV does not infect neurons directly. The molecular mechanisms by which HIV infection leads to neurocognitive decline are not fully understood, but several hypotheses have emerged to explain the development of neurocognitive impairment in HIV+ individuals. Two potential mechanisms by which HIV infection could interfere with normal brain functioning are (i) chemokine-induced neuroinflammation mediated by infected macrophages/microglia and (ii) direct neuronal toxicity induced by soluble HIV proteins (
      • Mattson M.P.
      • Haughey N.J.
      • Nath A.
      ). HIV-1-gp120, a glycoprotein that forms part of the envelope of HIV-1 particles, can be found in the cerebrospinal fluid of HIV+ individuals, and it has been shown to have neurotoxic effects in cell cultures (
      • Mattson M.P.
      • Haughey N.J.
      • Nath A.
      ,
      • Bardi G.
      • Sengupta R.
      • Kahn M.Z.
      • Patel J.P.
      • Meucci O.
      ,
      • Dreyer E.B.
      • Kaiser P.K.
      • Offerman J.T.
      • Lipton S.A.
      ,
      • Okamoto S.
      • Kang Y.J.
      • Brechtel C.W.
      • Siviglia E.
      • Russo R.
      • Clemente A.
      • Harrop A.
      • McKercher S.
      • Kaul M.
      • Lipton S.A.
      ,
      • Buzy J.
      • Brenneman D.E.
      • Pert C.B.
      • Martin A.
      • Salazar A.
      • Ruff M.R.
      ). HIV-1-gp120 interacts with several receptors found in the central nervous system (CNS), including CD4, CCR5, and CXCR4, as well as nicotinic acetylcholine receptors (nAChRs) (
      • Bracci L.
      • Lozzi L.
      • Rustici M.
      • Neri P.
      ,
      • Berger E.A.
      • Murphy P.M.
      • Farber J.M.
      ,
      • Lee C.
      • Liu Q.H.
      • Tomkowicz B.
      • Yi Y.
      • Freedman B.D.
      • Collman R.G.
      ). Several lines of evidence suggest the potential involvement of the nicotinic acetylcholine receptor α7-nAChR in HIV neuropathology (
      • Conejero-Goldberg C.
      • Davies P.
      • Ulloa L.
      ,
      • Giunta B.
      • Ehrhart J.
      • Townsend K.
      • Sun N.
      • Vendrame M.
      • Shytle D.
      • Tan J.
      • Fernandez F.
      ,
      • Rock R.B.
      • Gekker G.
      • Aravalli R.N.
      • Hu S.
      • Sheng W.S.
      • Peterson P.K.
      ); however, the role that nAChRs may play in the development of HAND has not been investigated.
      For HIV-1 to infect cells, it must bind the CD4 receptor and either the CCR5 or CXCR4 co-receptor. Interestingly, during the course of infection, HIV-1 evolves from an M-tropic (CCR5-dependent) variant that primarily infects macrophages to a T-tropic (CXCR4-dependent) variant that primarily infects T cells (
      • Berger E.A.
      • Murphy P.M.
      • Farber J.M.
      ,
      • Stalmeijer E.H.
      • Van Rij R.P.
      • Boeser-Nunninck B.
      • Visser J.A.
      • Naarding M.A.
      • Schols D.
      • Schuitemaker H.
      ). The increase in HIV particles with tropism for CXCR4 receptor correlates with the development of HAND (
      • Stalmeijer E.H.
      • Van Rij R.P.
      • Boeser-Nunninck B.
      • Visser J.A.
      • Naarding M.A.
      • Schols D.
      • Schuitemaker H.
      ,
      • Nieves D.M.
      • Plaud M.
      • Wojna V.
      • Skolasky R.
      • Meléndez L.M.
      ). Studies have shown that gp120 not only binds to CXCR4, but also activates its signaling pathway (
      • Missé D.
      • Cerutti M.
      • Noraz N.
      • Jourdan P.
      • Favero J.
      • Devauchelle G.
      • Yssel H.
      • Taylor N.
      • Veas F.
      ). CXCR4 activation by stromal cell-derived growth factor (SDF-1α), the endogenous agonist of CXCR4, has been shown to rapidly up-regulate the early growth response gene 1 (Egr-1), a transcription factor known to drive the expression of the α7-nAChR (
      • Luo Y.
      • Lathia J.
      • Mughal M.
      • Mattson M.P.
      ,
      • Criado M.
      • Domínguez del Toro E.
      • Carrasco-Serrano C.
      • Smillie F.I.
      • Juíz J.M.
      • Viniegra S.
      • Ballesta J.J.
      ). Furthermore, it has been shown that SDF-1α is secreted by astrocytes during inflammation and is increased in response to macrophage activation by HIV infection (
      • Peng H.
      • Erdmann N.
      • Whitney N.
      • Dou H.
      • Gorantla S.
      • Gendelman H.E.
      • Ghorpade A.
      • Zheng J.
      ). Consequently, we designed experiments to study the effects of gp120 on the expression and function of α7-nAChRs in SH-SY5Y neuroblastoma cells, which endogenously express α7-nAChRs and CXCR4 receptors (
      • Geminder H.
      • Sagi-Assif O.
      • Goldberg L.
      • Meshel T.
      • Rechavi G.
      • Witz I.P.
      • Ben-Baruch A.
      ). Our results show that CXCR4 activation, by gp120 or SDF-1α, leads to an increase in α7-nAChR activity that can culminate in cell death. In addition, Western blotting and quantitative RT-PCR analysis confirm up-regulation of α7-nAChR in transgenic mice expressing the HIV-gp120 gene.

      DISCUSSION

      We have developed a model for gp120 neurotoxicity, in which activation of the CXCR4 receptor by gp120 or SDF1 leads to activation of the MAPK pathway, increased EGR1 levels, and up-regulation of α7-nAChRs that triggers cell death (Fig. 6). This model is supported by data showing that treatment of SH-SY5Y cells with gp120 results in higher expression of α7-nAChRs, which are highly permeable to Ca2+. Increased intracellular Ca2+ can lead to cell death and has been associated with neuronal death in neurodegenerative diseases (
      • Marambaud P.
      • Dreses-Werringloer U.
      • Vingtdeux V.
      ). Along these lines, overexpression of α7-nAChRs has been shown to play a role in neurological disorders (
      • Counts S.E.
      • He B.
      • Che S.
      • Ikonomovic M.D.
      • DeKosky S.T.
      • Ginsberg S.D.
      • Mufson E.J.
      ). Studies have shown that in neuronal cultures, gp120 can induce an increase in Ca2+ levels, leading to neuronal injury, an effect that can be blocked with memantine (
      • Lipton S.A.
      ). Interestingly, besides being an antagonist for the NMDA receptor, memantine has been shown to also act as an antagonist of α7-nAChRs (
      • Aracava Y.
      • Pereira E.F.
      • Maelicke A.
      • Albuquerque E.X.
      ). Moreover, subsequent studies have shown involvement of CXCR4 in the neurotoxic effects of gp120 (
      • Aracava Y.
      • Pereira E.F.
      • Maelicke A.
      • Albuquerque E.X.
      ). These results suggest that other proteins, besides the NMDA receptor, contribute to gp120 neurotoxicity.
      Figure thumbnail gr6
      FIGURE 6Proposed mechanism for gp120-induced up-regulation of the α7-nAChR. Activation of CXCR4 by SDF-1 or gp120 causes activation of the Ras-Raf-MEK pathway. This leads to activation of Egr-1, a known transcription factor for the α7-nAChR gene (CHRNA7). Activation of Egr-1 leads to an increase in α7-nAChR mRNA levels.
      TUNEL staining showed that exposure to gp120 increases cell death in SH-SY5Y cells, consistent with previous studies (
      • Lipton S.A.
      ,
      • Catani M.V.
      • Corasaniti M.T.
      • Navarra M.
      • Nisticò G.
      • Finazzi-Agrò A.
      • Melino G.
      ). Our experiments show that pretreatment with α-bgtx reduced the percentage of cells undergoing cell death after gp120 treatment. These data suggest that the gp120-induced up-regulation of functional α7-nAChRs may be detrimental to neurons and implicates the α7-nAChR as a potential key player in HIV pathogenesis. It is important to mention that desensitization of α7-nAChRs by chronic exposure to different agonists, such as nicotine, has been associated to receptor up-regulation and neuroprotection (
      • Jonnala R.R.
      • Buccafusco J.J.
      ,
      • De Rosa M.J.
      • Esandi Mdel C.
      • Garelli A.
      • Rayes D.
      • Bouzat C.
      ). This scenario differs from the gp120-induced α7-nAChR up-regulation and toxicity in that the observed gp120 effects involve activation of the CXCR4 receptor. It is conceivable that chronic nicotine exposure leads to an increase in α7-nAChRs to compensate for the reduced receptor activity due to desensitization. In contrast, our data suggest that gp120 activates CXCR4 receptors, leading to an increase in functional α7-nAChRs without involving desensitization. Whereas small influxes in Ca2+ associated with tonic small levels of activation of α7-nAChRs might be neuroprotective, large influxes of Ca2+ as consequence of receptor up-regulation appear to be cytotoxic (
      • Johnson Jr., E.M.
      • Koike T.
      • Franklin J.
      ,
      • Uteshev V.V.
      • Meyer E.M.
      • Papke R.L.
      ).
      Many studies have shown that gp120 binding to the CXCR4 or CCR5 receptors elicits intracellular responses that include the activation of the MAPK pathway, transcription factors, and ion channels (
      • van der Meer P.
      • Ulrich A.M.
      • González-Scarano F.
      • Lavi E.
      ,
      • Liu Q.H.
      • Williams D.A.
      • McManus C.
      • Baribaud F.
      • Doms R.W.
      • Schols D.
      • De Clercq E.
      • Kotlikoff M.L.
      • Collman R.G.
      • Freedman B.D.
      ,
      • Stantchev T.S.
      • Broder C.C.
      ,
      • Del Corno M.
      • Liu Q.H.
      • Schols D.
      • de Clercq E.
      • Gessani S.
      • Freedman B.D.
      • Collman R.G.
      ). In the course of HIV infection, the virus exhibits changes in its tropism: from an R5 variant to an X4 variant (
      • Berger E.A.
      • Murphy P.M.
      • Farber J.M.
      ). By the time HIV-1 becomes capable of infecting cells through the use of the CXCR4, there is an associated CD4 cell decline and disease progression (
      • Stalmeijer E.H.
      • Van Rij R.P.
      • Boeser-Nunninck B.
      • Visser J.A.
      • Naarding M.A.
      • Schols D.
      • Schuitemaker H.
      ). This rapid decrease in CD4 cell count associated with CXCR4 tropism couples with an increased risk of developing HAND (
      • Giunta B.
      • Ehrhart J.
      • Townsend K.
      • Sun N.
      • Vendrame M.
      • Shytle D.
      • Tan J.
      • Fernandez F.
      ). This correlates with the fact that hippocampal and basal ganglia neurons express CXCR4 but not CCR5, which is present in glial cells (
      • van der Meer P.
      • Ulrich A.M.
      • González-Scarano F.
      • Lavi E.
      ). Previous studies have demonstrated that activation of CCR5 can lead to cell death in the presence of gp120 (
      • Kaul M.
      • Ma Q.
      • Medders K.E.
      • Desai M.K.
      • Lipton S.A.
      ); however, our experiments show that gp120IIIB as well as SDF-1α, both specific to CXCR4, induce an up-regulation of the α7-nAChR. Moreover, this effect is abolished by pretreatment with the CXCR4 antagonist AMD3100, ruling out the contribution of CCR5 in our experimental setting. These results show that CXCR4 activation is necessary for the up-regulation of α7-nAChRs, and CXCR4-expressing neurons would be more susceptible to the effects of HIV infection.
      CXCR4 activates the MAPK pathway, and its activation by SDF-1α induces the up-regulation of Egr-1, a transcription factor capable of stimulating the expression of the α7 gene (CHRNA7) (
      • Luo Y.
      • Lathia J.
      • Mughal M.
      • Mattson M.P.
      ,
      • Criado M.
      • Domínguez del Toro E.
      • Carrasco-Serrano C.
      • Smillie F.I.
      • Juíz J.M.
      • Viniegra S.
      • Ballesta J.J.
      ). Our experiments show that treating SH-SY5Y cells with SDF-1α induced a functional up-regulation of α7-nAChRs, as seen by increased α-bgtx binding and larger ACh-stimulated whole cell currents. Furthermore, quantitative RT-PCR experiments showed that gp120 and SDF-1α treatment of SH-SY5Y cells induced a rapid and transient increase in Egr-1 mRNA expression levels concomitant with an increase in α7-nAChRs mRNA expression levels. Together, these results provide a molecular mechanism as to how the α7-nAChR could be up-regulated in neurons in the context of an HIV-infected CNS.
      In HAND, the sustained immune response can produce neuronal injury despite viral control (
      • Woods S.P.
      • Moore D.J.
      • Weber E.
      • Grant I.
      ). In the brain, viral particles such as gp120 can cause macrophages and/or astrocytes to release various cytokines and chemokines (nitric oxide, TNF-α, IL-1, IL-6, monocyte chemoattractant protein 1), resulting in further neuronal stress and cell death. Production of IL-1 by astrocytes leads to an increase in SDF-1 (
      • Peng H.
      • Erdmann N.
      • Whitney N.
      • Dou H.
      • Gorantla S.
      • Gendelman H.E.
      • Ghorpade A.
      • Zheng J.
      ). The α7-nAChR has been shown to contribute to the regulation of inflammation in macrophages (the cholinergic anti-inflammatory pathway); however, the sustained immune response and increased production of SDF-1 could cause alterations in α7-nAChR function. Immune responses depend on the equilibrium between pro- and anti-inflammatory cytokines, and alterations of this equilibrium could convert a beneficial inflammatory response into a pathologic process (
      • Tyagi E.
      • Agrawal R.
      • Nath C.
      • Shukla R.
      ). In this context, gp120 and SDF-1 could have synergistic effects, leading to up-regulation of the α7-nAChR and subsequent neuronal death. Interestingly, a similar up-regulation of α7-nAChR has been observed in macrophages derived from HIV+ donors,
      L. Y. Ballester, C. M. Capó-Vélez, W. F. García-Beltrán, F. M. Ramos, E. Vázquez-Rosa, R. Ríos, J. R. Mercado, R. I. Meléndez, and J. A. Lasalde-Dominicci, unpublished data.
      but the implications of these findings for macrophage function and inflammation remain to be explored.
      To validate our results in an in vivo model, we used transgenic mice that express HIV-gp120 under the glial fibrillary acidic protein promoter. HIV-gp120 has been shown to induce neuropathological changes in mice similar to those seen in HAND patients (
      • Toggas S.M.
      • Masliah E.
      • Rockenstein E.M.
      • Rall G.F.
      • Abraham C.R.
      • Mucke L.
      ,
      • D'Hooge R.
      • Franck F.
      • Mucke L.
      • De Deyn P.P.
      ), making it a suitable model to study gp120-mediated neurotoxicity. Consistent with the results from in vitro experiments, we observed that α7-nAChR mRNA and protein levels are increased in the CNS of gp120-transgenic mice. However, the α7-nAChR up-regulation appears to be restricted to the striatum, a component of the basal ganglia and a region greatly affected in HAND patients (
      • Woods S.P.
      • Moore D.J.
      • Weber E.
      • Grant I.
      ).
      Our results are in agreement with experiments performed by Kaul et al. (
      • Kaul M.
      • Ma Q.
      • Medders K.E.
      • Desai M.K.
      • Lipton S.A.
      ) showing that gp120IIIB and SDF-1 are neurotoxic only in the presence of the CXCR4 receptor. In these experiments it was shown that inhibiting p38 prevented the gp120 and SDF-1 neurotoxicity. Interestingly, it has been shown that induction of Egr-1 requires p38 activity (
      • Kenzel S.
      • Santos-Sierra S.
      • Deshmukh S.D.
      • Moller I.
      • Ergin B.
      • Fitzgerald K.A.
      • Lien E.
      • Akira S.
      • Golenbock D.T.
      • Henneke P.
      ). These data, in conjunction with our results, suggest the existence of a neurotoxic pathway in which CXCR4 activation leads to a p38-dependent Egr-1 induction that increases α7-nAChR expression levels and causes cell death.
      In conclusion, our experiments suggest that the α7-nAChR is a previously unrecognized contributor to HIV neurotoxicity. Drugs that antagonize the CXCR4 or α7-nACh receptors might be of therapeutic benefit in the treatment of HAND.

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