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Review
. 2018 Oct;38(7):1335-1348.
doi: 10.1007/s10571-018-0603-8. Epub 2018 Jul 14.

Nicotinic Acetylcholine Receptors in HIV: Possible Roles During HAND and Inflammation

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Free PMC article
Review

Nicotinic Acetylcholine Receptors in HIV: Possible Roles During HAND and Inflammation

Coral M Capó-Vélez et al. Cell Mol Neurobiol. .
Free PMC article

Abstract

Infection with the human immunodeficiency virus (HIV) remains a threat to global health. Since its discovery, many efforts have been directed at understanding the mechanisms and consequences of infection. Although there have been substantial advances since the advent of antiretroviral therapy, there are still complications that significantly compromise the health of infected patients, particularly, chronic inflammation and HIV-associated neurocognitive disorders (HAND). In this review, a new perspective is addressed in the field of HIV, where the alpha7 nicotinic acetylcholine receptor (α7-nAChR) is the protagonist. We comprehensively discuss the available evidence implicating α7-nAChRs in the context of HIV and provide possible explanations about its role in HAND and inflammation in both the central nervous system and the periphery.

Keywords: Gp120; HAND; HIV; Inflammation; Nicotinic acetylcholine receptor.

Conflict of interest statement

The authors declare that there is no conflict of interest.

Figures

Fig. 1
Fig. 1
Effects of HIV infection on macrophages’ α7-nAChRs. a In uninfected macrophages, SDF-1α promotes signaling through CXCR4, a G-protein coupled receptor. In addition, as mentioned before, α7-nAChR is sensitive to the antagonist α-bgtx. A robust body of evidence demonstrates that the net effect of α7-nAChR activation is inhibition of the production of cytokines (Wang et al. 2003), consequently decreasing inflammation (efficient CAP). Whether the ion influx through α7-nAChR is relevant for the proper operation of the CAP or other important physiological processes remains obscure. b In infected macrophages, HIV-infected CD4+ T-lymphocytes secrete virions and gp120IIIB that interact and stimulate CXCR4 to induce the upregulation of α7-nAChR (Delgado-Vélez et al. 2015). This upregulation does not result in cell death, or apoptosis, which is consistent with the anti-apoptotic signature expressed by monocytes recovered from patients infected with HIV (Giri et al. 2009) and those from HIV-infected macrophages (Swingler et al. 2007). Contrary to what was expected, the activation of this high number of α7-nAChRs with ACh does not enhance the CAP response because their activation does not lead to inhibition of cytokine production, therefore, conferring macrophages a proinflammatory phenotype indicative of a CAP disruption. Moreover, application of an antagonist of α7-nAChR, bupropion, partially restores the CAP by reducing inflammatory chemokines, but not interleukins (Delgado-Vélez et al. 2015). Interestingly, whether the identity of the non-selective calcium channel previously described (Liu et al. 2000) is α7-nAChR remains to be determined
Fig. 2
Fig. 2
Effects of HIV infection on neurons’ α7-nAChRs. 14 gp120 released from HIV-infected microglia interact with CXCR4 expressed by neurons, activating the Ras/Raf/MEK/Erk/Egr-1 signaling pathway that eventually promotes α7-nAChR upregulation in neuronal cells (Ballester et al. 2012). Moreover, this response can be recapitulated by adding SDF-1α, the endogenous agonist of CXCR4, which also induces α7-nAChR overexpression in neuronal cells (Ballester et al. 2012). These responses are sensitive to CXCR4 blockade with AMD3100 and MEK inhibition by U0126 or PD98059. 5 Furthermore, α7-nAChR activation with ACh promotes intracellular Ca2+ overload that results in cell death and apoptosis (Ballester et al. ; Capó-Vélez et al. 2018). 6 The gp120-induced α7-nAChR upregulation described in points 15 involves a decrease in dupα7 expression, its repressive partial duplication (Ramos et al. 2015)

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