The α7‐nicotinic receptor is upregulated in immune cells from HIV‐seropositive women: consequences to the cholinergic anti‐inflammatory response

Abstract

Antiretroviral therapy partially restores the immune system and markedly increases life expectancy of HIV-infected patients. However, antiretroviral therapy does not restore full health. These patients suffer from poorly understood chronic inflammation that causes a number of AIDS and non-AIDS complications. Here we show that chronic inflammation in HIV+ patients may be due to the disruption of the cholinergic anti-inflammatory pathway by HIV envelope protein gp120IIIB. Our results demonstrate that HIV gp120IIIB induces α7 nicotinic acetylcholine receptor (α7) upregulation and a paradoxical proinflammatory phenotype in macrophages, as activation of the upregulated α7 is no longer capable of inhibiting the release of proinflammatory cytokines. Our results demonstrate that disruption of the cholinergic-mediated anti-inflammatory response can result from an HIV protein. Collectively, these findings suggest that HIV tampering with a natural strategy to control inflammation could contribute to a crucial, unresolved problem of HIV infection: chronic inflammation.

Cigarette smoke and nicotine effects on brain proinflammatory responses and behavioral and motor function in HIV-1 transgenic rats

“…However, chronic nicotine exposure can result in desensitization of the receptor in association with an increase in receptor numbers, and, paradoxically, an increase in proinflammatory responses (Marks et al 1993). Similarly, HIV gp120 has been demonstrated to also upregulate microglial cell nicotinic acetyl choline receptor expression in association with downregulation of receptor function and suppression of anti-inflammatory cholinergic responses (Delgado-Velez et al 2015). These effects could potentially result in nicotine inducing an overall enhancement of inflammatory responses, which could exacerbate the nervous system damage that can occur in HIV-infected individuals.…”

Modulatory Effects of Nicotine on neuroHIV/neuroAIDS

“…Given these many existing similarities among HAND and other neural disorders, nicotine may play similar roles in HAND, which will attenuate the effects of HIV infection on neurocognitive disorders. A recent study showed that α7 nAChR is upregulated in HIV-seropositive individuals (Delgado-Velez et al 2015). Bupropion, an α7 nAChR antagonist, partially mitigates inflammation in HIV infection, suggesting that α7 nAChR is an attractive anti-inflammatory therapeutic target to counteract the chronic inflammation suffered by HIV-infected patients (Delgado-Velez et al 2015).…”

“…A recent study showed that α7 nAChR is upregulated in HIV-seropositive individuals (Delgado-Velez et al 2015). Bupropion, an α7 nAChR antagonist, partially mitigates inflammation in HIV infection, suggesting that α7 nAChR is an attractive anti-inflammatory therapeutic target to counteract the chronic inflammation suffered by HIV-infected patients (Delgado-Velez et al 2015). However, to our knowledge, there are few studies on the protective effects of nicotine in the presence of HIV-1 infection, for which the underlying mechanism remains to be determined.…”

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

“…Cytokines are key to innate immune responses; however, excessive cytokine production can give rise to chronic or uncontrolled inflammatory responses, an event related to the pathology of many inflammatory diseases (Johnston and Webster 2009 ; Wang et al 2009 ). Inflammation is controlled through the cholinergic anti-inflammatory pathway (CAP), which seems to be altered in HIV patients (Delgado-Vélez et al 2015 ). In non-infected patients, impairment or disruption of the CAP is associated with delirium, depression, ulcerative colitis, postoperative cognitive decline, inflammatory bowel disease, hemorrhagic shock, pancreatitis, exacerbation of ventilator-induced lung injury, septic peritonitis, hypotensive shock, and cardiopulmonary arrest (Lindgren et al 1993 ; Borovikova et al 2000 ; van Westerloo et al 2005 , 2006 ; Das 2007 ; Tracey 2009 ; dos Santos et al 2011; Norman et al 2011 , Su et al 2012 ; Cerejeira et al 2012 ).…”

“…Specifically, several studies have presented evidence implicating ion channels in HIV infection (Raber et al 1996 ; Holden et al 1999 ; Gelman et al 2004 ; Herman et al 2010 ; Chen et al 2011 ; Liu et al 2013 ; Tewari et al 2015 ), suggesting that they could be used as potential pharmacological targets. Among these ion channels, nicotinic acetylcholine receptors (nAChRs) have been suggested to play important roles (Bracci et al 1992 ; Giunta et al 2004 ; González-Lira et al 2006 ; Rock et al 2008 ; Ballester et al 2012 ; Cao et al 2013 ; Gundavarapu et al 2013 ; Zhang et al 2015 ; Báez-Pagán et al 2015 ; Ramos et al 2015 ; Delgado-Vélez et al 2015 ; Liu et al 2017 ; Ekins et al 2017 ; Capó-Vélez et al 2018 ); however, these have not yet been extensively explored. In particular, the α7-nAChR is emerging as an important player in the HIV field, since it is expressed not only in the brain, but also in a wide variety of immune cells that are targeted during HIV infection, such as macrophages, monocytes, B-lymphocytes, and T-lymphocytes (CD4 + ) (Wang et al 2003 ; van der Zanden et al 2012 ; Kawashima et al 2015 ), making it a suitable target for treatment development.…”