J Neuroimmune Pharmacol DOI 10.1007/s11481-014-9554-0
PERSPECTIVE
Cannabinoid Receptor-2 and HIV-Associated Neurocognitive Disorders Vishnudutt Purohit & Rao S. Rapaka & Joni Rutter
Received: 24 June 2014 / Accepted: 2 July 2014 # Springer Science+Business Media New York (outside the USA) 2014
Abstract Despite the wide spread use of highly active antiretroviral therapy (HAART), mild forms of HIV-associated neuro cognitive disorders (HAND) remain commonplace. HAART treated patients now show low levels of viremia and more subtle yet biologically important signs of brain macrophage and microglial activation. Adjunctive therapeutic strategies are required to eliminate HIV-1 infection and suppress immune activation and its associated neuroinflammation. In this regard, cannabinoid receptor-2(CB2) activation is a promising means to attenuate HAND by inhibiting HIV replication, down regulating inflammation, and suppressing chemokine-like activity of viral neurotoxic proteins (for example, Tat and HIV1gp120), and thereby prevent neuronal and synaptic loss. Inhibiting even low level HIV replication can attenuate neuronal injury by decreasing the production of neurotoxins. Down regulation of inflammation by CB2 activation is mediated through blunted activation of peri vascular macrophages and microglia; decreased production of tumor necrosis factor-α, chemokines and virotoxins. Down regulated neuroinflammation can decrease blood brain barrier permeability and leukocyte infiltration resulting in reduced neuronal injury. It is suggested that CB2 agonists may further attenuate HAND in HIVinfected patients on HAART. In addition, CB2 activation may also blunt brain injury by attenuating drug addiction. Keywords HIV-associated neurocognitive disorders . Highly active antiretroviral therapy . Cannabinoid receptor type 2 . Neuroinflammation . Macrophages and microglia . Blood brain barrier V. Purohit (*) : R. S. Rapaka : J. Rutter Chemistry and Physiological Systems Research Branch Division of Basic Neuroscience & Behavioral Research, National Institute on Drug Abuse National Institutes of Health, 6001 Executive Blvd., NSC Bldg. - Rm 4275, 20892 Bethesda, MD, USA e-mail: [email protected]
Introduction The neurological complication of AIDS results from chronic human immunodeficiency virus type one (HIV-1) infection and associated inflammation and neurodegeneration (Tan and McArthur 2012; Shapshak et al. 2011). The clinical features of disease are predominantly neuro cognitive impairments that include decreased attention, concentration, psychomotor speed, memory, learning, information processing and executive function. Collectively they are termed as HIV-associated neuro cognitive disorders (HAND) (Clifford and Ances 2013). HIV-associated dementia (HAD) is its most severe form characterized by significant impairment in cognitive function, especially in learning of new information, information processing, attention or concentration, and functional impairment. Although use of highly active antiretroviral therapy (HAART) has significantly reduced the incidence of HAD (Sacktor et al. 2002; Bhaskaran et al. 2008), milder form of HAND occurs in about half of infected patients (Heaton 2010; McArthur et al. 2010). This condition can have significant effects on employment, medication adherence, and other activities of daily living (Grant 2008). In even the mild form of HAND, HIV infected patients continue to demonstrate low levels of plasma viremia (Palmer et al. 2008; Maldarelli et al. 2007) and signs of innate immune activation (Eden et al. 2007; Spudich et al. 2011). Therefore, therapeutic strategies are required to develop adjunct therapies, along with HAART, to further prevent HIV-1 replication and suppress immune activation and associated neuroinflammation. The pathogenesis of HAND was previously discussed by others (Alfahad and Nath 2013; Tan and McArthur 2012; Suh et al. 2014; Gonzalez-Scarano and Martin-Garcia 2005; Gannon et al. 2011). In brief, HIV enters the brain mediated by transmigration of infected monocytes across the blood
brain barrier (BBB) within weeks of systemic infection (Davis et al. 1992; An et al. 1999). In the brain, chronic productive HIV-1 infection is established in peri vascular macrophages that results in increased production of virus and associated release of viral products including Tat and gp120 and cellular pro-inflammatory factors which can cause neuronal injury (Kraft-Terry et al. 2009; Gonzalez-Scarano and Martin-Garcia 2005; Rumbaugh and Nath 2006). Stimulation of brain mononuclear phagocytes (macrophages and microglia) leads to secretion of neurotoxic products such as proinflammatory cytokines, quinolinic acid, arachidonic acid, and nitric oxide (Kraft-Terry et al. 2010; GonzalezScarano and Martin-Garcia 2005). Increased release of viral and non viral toxic products from infected macrophage/ microglia can result in increased oxidative stress, increased release of chemokines, increased expression of adhesion molecules, increased BBB permeability, increased migration of HIV-infected cells into the brain, and subsequent neuronal injury.
CB2 and HIV Replication The role of CB2 receptor activation in HIV replication has been investigated in various susceptible cells, including CD4 + T cells, microglia, and macrophages (Peterson et al. 2004; Rock et al. 2007; Costantino et al. 2012; Ramirez et al. 2013). There are two well-characterized cannabinoid receptors with different physiological properties. The psychoactive effects of cannabinoids are primarily mediated through cannabinoid receptor-1 (CB1), whereas cannabinoid receptor-2 (CB2) mainly mediates anti-inflammatory and immunomodulatory actions (Miller and Stella 2008). However, recently CB2 receptor has been shown to express in neurons and modulate addictive properties of cocaine (Xi et al. 2011; AracilFernandez et al. (2012). The purpose of this report is to discuss the role of CB2 receptor activation in the attenuation of HAND via inhibition of HIV replication, suppression of inflammation, and attenuation of synapse damage in the brain. Peterson et al. (2004) investigated the role of a synthetic cannabinoid WIN 55, 212, 2 (a dual agonist for both CB1 and CB2 receptors) on HIV-1 expression in CD4+ T lymphocytes and microglial cells. The WIIN 55, 212,2 attenuates HIV-1 p24 expression by approximately 60 %. Subsequently, using CB1 and CB2 selective agonists and antagonists, it was discovered that the inhibitory effect of WIN 55,212,2 on HIV replication in microglial cells was mediated through CB2 receptor activation (Rock et al. 2007).
CB2 receptor activation by a selective agonist JWH-133 was shown to reduce CXCR4-tropic infection in primary CD4 + T cells (Costantino et al. 2012). These investigators used a GFP-expressing variant of the CXCR4-tropic lab isolate NL4.3 (NL-GI), in which GFP is expressed in place of the viral gene nef, to assay HIV-1 infectivity. Recently, Ramirez et al. (2013) investigated the role of CB2 activation on HIV replication in macrophages. In this study, CB2 agonists (JWH133, GP1a, and O-1966) significantly attenuated HIV replication in human monocyte-derived macrophages (MDM) as shown by decreased reverse transcriptase activity. These findings were associated with partial inhibition of the expression of HIV-1 pol and marked decrease in HIV-1 LTR, suggesting that CB2 activation targets various steps of HIV-1 replication. Taken together, in vitro studies suggest that CB2 agonists have potential to inhibit HIV replication. It is not clear whether CB2 activation attenuates HIV replication via modulating the expression of HIV coreceptors (CCR5 or CXCR4). Gorantla et al. (2010) reported reduced expression of CCR5 expression on CD4+ T cells with Gp1a (a CB2 agonist) treatment in hu-PBL and huPBL/HIVE mice compared to non-treated animal groups, suggesting that CB2 activation may inhibit viral replication via inhibiting viral entry. However, Ramirez et al. (2013) did not observe any significant effect of CB2 agonists (JWH133 and GP1a) on the expression of CCR5 or CXCR4 receptors in MDM. Whether CB2 activation can attenuate HIV replication in vivo system is not known. In a simian immunodeficient virus (SIV) study, chronic delta 9 THC (partial CB1/CB2 agonist) administration attenuated plasma and cerebrospinal fluid (CSF) viral load in the infected animals and in vitro THC decreased SIV replication in human T cell line MT4-R5 cells (Molina et al. 2011). These authors did not examine whether the effect was mediated through CB1 or CB2 receptor. In a randomized placebo-controlled clinical trial in HIV-infected patients, short- term marijuana exposure (21 days) was associated with a reduction in viral load (Abrams et al. 2003). The role of CB2 receptors cannot be ascertained from this study since marijuana exposure is expected to activate both CB1 and CB2 receptors. Whether CB2 agonists can inhibit HIV replication in humans is not known. In vitro studies discussed above suggest that CB2 agonists can inhibit HIV replication in macrophages and microglia. Thus, CB2 activation has potential to further reduce or eliminate HIV replication in the brain of HIVinfected patients who are on HAART. Further studies are required to determine the role of CB2e receptor activation in HIV replication in vivo system.
CB2 and Inflammation CB2 receptor activation has been shown to reduce inflammatory responses in various cells types, particularly those of immune system (Pini et al. 2012). Gorantla et al. (2010) evaluated the role of CB2 receptor activation in the attenuation of HIV-induced brain inflammation using a murine model of neuroAIDS. In this model, encephalitis is produced in mice by injecting HIV-1-infected human MDM into the brain of immunodeficient mice reconstituted with human peripheral blood lymphocytes (hu-PBL/HIVE). The encephalitis is characterized by increased infiltration of human cells (HLA-DQ expression) into mouse brain, increased microglial activation as shown by increased expression of Mac-1 (CD11b), and increased expression of inflammatory cytokine tumor necrosis factor-α (TNFα). Treatment with a selective CB2 receptor agonist, Gp1a, significantly reduced expression of HLA-DQ, Mac-1, and TNFα. Suppression of microglial activation and reduced TNFα production by CB2 receptor activation has also been reported by other investigators (Ehrhart et al. 2005; Facchinetti et al. 2003; Puffenbarger et al. 2000). CB2 receptor agonists may suppress leukocyte trafficking through BBB by reducing rolling and infiltration into inflamed areas (Xu et al. 2007) and/or by reducing the expression of endothelial cell adhesion molecules required for transmigration (Burstein et al. 1992; Mestre et al. 2009). Since inflammation is primarily responsible for HIV-1associated neuronal damage, CB2 agonist treatment has potential to down regulate inflammatory changes that may attenuate HAND.
potent chemoattractant for monocytes (Mitola et al. 1997; Albini et al. 1998). Because of these properties, Tat has been implicated in HIV neuro pathogenesis. Fraga et al. (2011) investigated the role of delta-9 tetrahydrocannabinol (THC) and CP55940 (dual cannabinoid agonist for CB1 and CB2 receptors) in the migration of mouse BV-2 microglial cells towards Tat. Both cannabinoids significantly inhibited the migration of BV-2 cells towards Tat. A similar inhibitory response was obtained when the endogenous cannabinoid 2-arachidonoylglycerol was used. The inhibition of Tat migration was blocked by the CB2 receptor antagonist SR144528, but not by the CB1 receptor antagonist SR141716A. Similarly, CB2 receptor knockdown with small interfering RNA reversed the cannabinoid-mediated inhibition. In a similar study, THC and CP55940 were shown to significantly inhibit migration of human U937 macrophage-like cells to the Tat protein in a concentration-related manner (Raborn and Cabral 2010). Using selective CB1 and CB2 receptor agonists and antagonists, these researchers showed that the inhibitory effect of cannabinoid on the macrophage migration to Tat was mediated via CB2 receptor activation. In addition, the level of the β-chemokine receptor CCR-3 was reduced and its intracellular compartmentation was altered. These results indicate that cannabinoid-mediated inhibition of BV-2 microglial-like or macrophage-like cell migration to Tat is mediated through CB2 receptor activation. Therefore, CB2 may attenuate HAND by down-regulating neuroinflammation by blocking chemokine-like activity of Tat.
CB2 and BBB Integrity CB2 and Chemokine-Like Activity of Tat Chemokines play an important role in the initiation of inflammatory process by triggering the migration of inflammatory leukocytes from the peripheral circulation into various organs. HIV-1 Tat (trans-activating factor) is a regulatory protein that exhibits beta chemokine-like activity (Albini et al. 1998; de Paulis et al. 2000) and it has been shown to displace binding of beta chemokines from the beta chemokine receptors CCR2 and CCR3 (Albini et al. 1998). Tat is highly immunogenic and induces the production of proinflammatory cytokines and chemokines in astrocytes (El-Hage et al. 2006), monocytes (Lafrenie et al. 1997), microglia (Minghetti et al. 2004), and T lymphocytes (Kim et al. 2004). Tat-activated monocytes upregulate cell surface adhesion molecules, including vascular cell adhesion molecule-1 and intercellular adhesion molecule1 (Pu et al. 2003). In addition, it has been reported that Tat is a
The BBB is a dynamic interphase between the peripheral circulation and the central nervous system (CNS) and it is composed of microvascular endothelium, astrocytes, and pericytes. Impairment of BBB integrity has been linked to various inflammatory brain diseases such as Alzheimer, multiple sclerosis (Persidsky et al. 2006), and it plays an important role in the pathogenesis of HAND where inflammatory mediators are primarily responsible for the breakdown of BBB integrity (Avison et al. 2004). While investigating the role of CB2 receptors in the attenuation of TNFα-induced changes in coronary artery endothelial cells, Rajesh et al. (2007) discovered that activation of CB2 receptors by CB2 agonist JWH 133 or HU 308 attenuated TNFα-induced transendothelial migration of monocytes, which could partially be attributed to the restoration of the integrity of endothelial cell junctions. Subsequently, Ramirez et al. (2012) investigated the role of CB2 activation on BBB integrity under inflammatory
conditions using a mouse model of lipopolysaccharide (LPS)induced encephalitis. In this study, CB2 agonists (JWH133, and O-1966) prevented LPS-induced barrier leakiness and this was associated with an increase in transendothelial electrical resistance and tight junction proteins. These results suggest that CB2 activation may protect BBB integrity from neuroinflammation and thereby attenuate HAND. Interestingly, Lu et al. (2008) did not observe significant effect of CB2 activation on BBB permeability. This discrepancy could be due to the fact that these researchers investigated the effects of cannabinoid receptor activation under noninflammatory condition where CB1, but not CB2, activation was shown to decrease gp120-induced increased BBB permeability by up-regulating the expression of tight junction proteins.
CB2 and Dendritic/Synapse Injury HIV-1 infection of the CNS results in dendritic pruning and a reduction in spine density and these changes are correlated with cognitive impairment in AIDS patients (Sa et al. 2004). GP120 produces dendritic pruning and loss of spines when applied to neurons in culture or expressed in transgenic animals (Toggas et al. 1994; Viviani et al. 2006). In addition, Tat has been shown to induce synapse loss between hippocampal neurons in culture (Kim et al. 2008a) and impair synapse function when expressed in transgenic mice (Fitting et al. 2013). Since cannabinoid receptor agonists prevented or even reversed synapse loss induced by intense excitatory synaptic activity (Kim et al. 2008b), these researchers investigated whether cannabinoids can prevent synapse loss between cultured hippocampal neurons induced by HIV proteins Tat and gp120 (Kim et al. 2011). In this study, morphology and synapses between cultured hippocampal neurons were visualized by confocal imaging of neurons expressing DsRed2 and postsynaptic density protein 95 fused to green fluorescent protein (PSD95-GFP). The synaptic network that forms between hippocampal neurons in culture was significantly degraded after exposure to the HIV envelope protein gp120 for 24 h and the synapse loss preceded neuronal cell death. Mechanistic studies revealed that sequential activation of CXCR4, the interleukin-1β (IL-1β) receptor, the N-methylD-aspartate receptor, and ubiquitin ligase was required for the gp120-induced synapse loss. The cannabinoid full agonist Win55,212,2 inhibited gp120-induced, but not Tat-induced, synapse loss. This can be reversed by CB2 receptors antagonist, suggesting that the effect of cannabinoid is mediated via CB2 receptor activation. These results indicate that CB2 receptor agonist has potential to attenuate or reverse the
cognitive decline in HAND patients by preventing gp120induced loss of synapse.
CB2 and Cocaine Addiction Cocaine use is a risk factor for HIV infection and it contributes to the progression of AIDS (Fiala et al. 1998; Larrat and Zierler 1993; Webber et al. 1999). Similar to HIV infection, cocaine use/addiction can also lead to the development of neurocognitive disorders (Beatty et al. 1995; Ardila et al. 1991; Rosselli et al. 2001; Verdejo-Garcia and Perez-Garcia 2007). Furthermore, cocaine use has been shown to exacerbate neurocognitive impairment in HIV patients (Levine et al. 2006; Meade et al. 2011). Therefore, in cocaine-abusing HIV patients, attenuation of cocaine addiction may help reduce the severity of HAND. Interestingly, CB2 receptor activation has been shown to attenuate cocaine addiction in experimental animals (Xi et al. 2011; Aracil-Fernandez et al. (2012). Xi et al. (2011) reported that systemic, intranasal or intra-accumbens administration of JWH133 (a selective CB2 receptor agonist) inhibits intravenous cocaine self-administration, and attenuates cocaine-enhanced accumbens dopamine in wild-type and CB1 receptor-knockout (CB1−/−), but not in CB2−/−, mice. In addition, Intra-accumbens JWH133 alone decreased, while intra-accumbens AM630 (a selective CB2 antagonist) elevated, extracellular dopamine in wild type and CB1−/−mice, but not in CB2−/−mice. Intra-accumbens AM630 also blocked the reduction in cocaine selfadministration and extracellular dopamine produced by systemic administration of JWH133. Similar findings were reported by Aracil-Fernandez et al. (2012) in that cocaine intravenous self-administration was significantly less in CB2 overexpressing mice when compared to wild type mice. Importantly, CB2 overexpressing mice exhibited cocaine-induced conditioned place aversion. Moreover, they detected the presence of CB2 receptors in neurons and astrocytes which were colocalized with D2 dopamine receptors in the ventral tegmental area and nucleus accumbens. These findings suggest that brain CB2 receptors modulate cocaine’s rewarding effects, which appears to be dopamine-dependent. Since CB2 receptor activation has been shown to attenuate some of the pathological features that underlie the development of HAND, and reduce cocaine self-administration in experimental animals, treatment with CB2 agonist may have potential to treat HAND directly as well as indirectly by attenuating cocaine addiction.
Fig. 1 CB2 activation may attenuate HAND by inhibiting HIV replication, down regulating inflammation, inhibiting chemokine-like activity of Tat, and preventing synapse loss. Inhibited HIV replication can attenuate neuronal injury by decreasing the production of neurotoxic HIV proteins, Tat and HIV-1gp120. Down regulation of inflammation is mediated through blunted activation of macrophage/ microglia; decreased production of TNFα, chemokines, and adhesion molecules; and reduced chemokine-like activity of Tat. Down regulated inflammation can decrease BBB permeability and leukocyte infiltration resulting in reduced neuronal injury
Role of CB2 Receptor Activation in the Attenuation of HAND CB2 Activation
HIV replication (macrophage/ Microglia/ CD4 +T cells)
Macrophage/ microglia activation
Chemokine-like Tat activity
Synapse loss
TNF /chemokine/ adhesion molecule
Tat and gp120 Inflammation BBB permeability Leukocyte infiltration Neuronal injury
HAND
Summary
References
A summary of the role of CB2 activation has been presented in Fig. 1. CB2 receptor activation can attenuate HAND severity by inhibiting HIV replication, blunting HIV-triggered neuroinflammation, preventing HIV-induced damage to BBB integrity, and preventing HIV-associated synapse loss. CB2 receptor activation may inhibit HIV replication in peri vascular macrophages, microglia, and CD4+ T cells. This is expected to decrease the production of neurotoxic HIV products. CB2 receptor activation can disrupt HIV-triggered inflammatory cascade including down regulating activation of brain innate immunity, inhibiting production of proinflammatory cytokines (for example, TNFα, IL-1β), blunting chemokine activity of Tat and other chemokines, down regulating the expression of adhesion molecules, and blocking brain transmigration of HIVinfected leukocytes. Blunting inflammation appears to be a mechanism whereby CB2 receptor activation prevents HIVinduced damage to BBB integrity. CB2 receptor activation may also minimize neuronal loss, and thus attenuate HAND, by blocking gp120-induced synapse loss directly and indirectly by reducing the production of Tat and gp120 via suppressing HIV replication. Finally, in cocaine-abusing HIV patients, attenuation of cocaine addiction by CB2 receptor activation may help reduce the clinical manifestations of HAND.
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Conflict of Interest Statement Authors declare no conflict of interest.
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PERSPECTIVE
Cannabinoid Receptor-2 and HIV-Associated Neurocognitive Disorders Vishnudutt Purohit & Rao S. Rapaka & Joni Rutter
Received: 24 June 2014 / Accepted: 2 July 2014 # Springer Science+Business Media New York (outside the USA) 2014
Abstract Despite the wide spread use of highly active antiretroviral therapy (HAART), mild forms of HIV-associated neuro cognitive disorders (HAND) remain commonplace. HAART treated patients now show low levels of viremia and more subtle yet biologically important signs of brain macrophage and microglial activation. Adjunctive therapeutic strategies are required to eliminate HIV-1 infection and suppress immune activation and its associated neuroinflammation. In this regard, cannabinoid receptor-2(CB2) activation is a promising means to attenuate HAND by inhibiting HIV replication, down regulating inflammation, and suppressing chemokine-like activity of viral neurotoxic proteins (for example, Tat and HIV1gp120), and thereby prevent neuronal and synaptic loss. Inhibiting even low level HIV replication can attenuate neuronal injury by decreasing the production of neurotoxins. Down regulation of inflammation by CB2 activation is mediated through blunted activation of peri vascular macrophages and microglia; decreased production of tumor necrosis factor-α, chemokines and virotoxins. Down regulated neuroinflammation can decrease blood brain barrier permeability and leukocyte infiltration resulting in reduced neuronal injury. It is suggested that CB2 agonists may further attenuate HAND in HIVinfected patients on HAART. In addition, CB2 activation may also blunt brain injury by attenuating drug addiction. Keywords HIV-associated neurocognitive disorders . Highly active antiretroviral therapy . Cannabinoid receptor type 2 . Neuroinflammation . Macrophages and microglia . Blood brain barrier V. Purohit (*) : R. S. Rapaka : J. Rutter Chemistry and Physiological Systems Research Branch Division of Basic Neuroscience & Behavioral Research, National Institute on Drug Abuse National Institutes of Health, 6001 Executive Blvd., NSC Bldg. - Rm 4275, 20892 Bethesda, MD, USA e-mail: [email protected]
Introduction The neurological complication of AIDS results from chronic human immunodeficiency virus type one (HIV-1) infection and associated inflammation and neurodegeneration (Tan and McArthur 2012; Shapshak et al. 2011). The clinical features of disease are predominantly neuro cognitive impairments that include decreased attention, concentration, psychomotor speed, memory, learning, information processing and executive function. Collectively they are termed as HIV-associated neuro cognitive disorders (HAND) (Clifford and Ances 2013). HIV-associated dementia (HAD) is its most severe form characterized by significant impairment in cognitive function, especially in learning of new information, information processing, attention or concentration, and functional impairment. Although use of highly active antiretroviral therapy (HAART) has significantly reduced the incidence of HAD (Sacktor et al. 2002; Bhaskaran et al. 2008), milder form of HAND occurs in about half of infected patients (Heaton 2010; McArthur et al. 2010). This condition can have significant effects on employment, medication adherence, and other activities of daily living (Grant 2008). In even the mild form of HAND, HIV infected patients continue to demonstrate low levels of plasma viremia (Palmer et al. 2008; Maldarelli et al. 2007) and signs of innate immune activation (Eden et al. 2007; Spudich et al. 2011). Therefore, therapeutic strategies are required to develop adjunct therapies, along with HAART, to further prevent HIV-1 replication and suppress immune activation and associated neuroinflammation. The pathogenesis of HAND was previously discussed by others (Alfahad and Nath 2013; Tan and McArthur 2012; Suh et al. 2014; Gonzalez-Scarano and Martin-Garcia 2005; Gannon et al. 2011). In brief, HIV enters the brain mediated by transmigration of infected monocytes across the blood
brain barrier (BBB) within weeks of systemic infection (Davis et al. 1992; An et al. 1999). In the brain, chronic productive HIV-1 infection is established in peri vascular macrophages that results in increased production of virus and associated release of viral products including Tat and gp120 and cellular pro-inflammatory factors which can cause neuronal injury (Kraft-Terry et al. 2009; Gonzalez-Scarano and Martin-Garcia 2005; Rumbaugh and Nath 2006). Stimulation of brain mononuclear phagocytes (macrophages and microglia) leads to secretion of neurotoxic products such as proinflammatory cytokines, quinolinic acid, arachidonic acid, and nitric oxide (Kraft-Terry et al. 2010; GonzalezScarano and Martin-Garcia 2005). Increased release of viral and non viral toxic products from infected macrophage/ microglia can result in increased oxidative stress, increased release of chemokines, increased expression of adhesion molecules, increased BBB permeability, increased migration of HIV-infected cells into the brain, and subsequent neuronal injury.
CB2 and HIV Replication The role of CB2 receptor activation in HIV replication has been investigated in various susceptible cells, including CD4 + T cells, microglia, and macrophages (Peterson et al. 2004; Rock et al. 2007; Costantino et al. 2012; Ramirez et al. 2013). There are two well-characterized cannabinoid receptors with different physiological properties. The psychoactive effects of cannabinoids are primarily mediated through cannabinoid receptor-1 (CB1), whereas cannabinoid receptor-2 (CB2) mainly mediates anti-inflammatory and immunomodulatory actions (Miller and Stella 2008). However, recently CB2 receptor has been shown to express in neurons and modulate addictive properties of cocaine (Xi et al. 2011; AracilFernandez et al. (2012). The purpose of this report is to discuss the role of CB2 receptor activation in the attenuation of HAND via inhibition of HIV replication, suppression of inflammation, and attenuation of synapse damage in the brain. Peterson et al. (2004) investigated the role of a synthetic cannabinoid WIN 55, 212, 2 (a dual agonist for both CB1 and CB2 receptors) on HIV-1 expression in CD4+ T lymphocytes and microglial cells. The WIIN 55, 212,2 attenuates HIV-1 p24 expression by approximately 60 %. Subsequently, using CB1 and CB2 selective agonists and antagonists, it was discovered that the inhibitory effect of WIN 55,212,2 on HIV replication in microglial cells was mediated through CB2 receptor activation (Rock et al. 2007).
CB2 receptor activation by a selective agonist JWH-133 was shown to reduce CXCR4-tropic infection in primary CD4 + T cells (Costantino et al. 2012). These investigators used a GFP-expressing variant of the CXCR4-tropic lab isolate NL4.3 (NL-GI), in which GFP is expressed in place of the viral gene nef, to assay HIV-1 infectivity. Recently, Ramirez et al. (2013) investigated the role of CB2 activation on HIV replication in macrophages. In this study, CB2 agonists (JWH133, GP1a, and O-1966) significantly attenuated HIV replication in human monocyte-derived macrophages (MDM) as shown by decreased reverse transcriptase activity. These findings were associated with partial inhibition of the expression of HIV-1 pol and marked decrease in HIV-1 LTR, suggesting that CB2 activation targets various steps of HIV-1 replication. Taken together, in vitro studies suggest that CB2 agonists have potential to inhibit HIV replication. It is not clear whether CB2 activation attenuates HIV replication via modulating the expression of HIV coreceptors (CCR5 or CXCR4). Gorantla et al. (2010) reported reduced expression of CCR5 expression on CD4+ T cells with Gp1a (a CB2 agonist) treatment in hu-PBL and huPBL/HIVE mice compared to non-treated animal groups, suggesting that CB2 activation may inhibit viral replication via inhibiting viral entry. However, Ramirez et al. (2013) did not observe any significant effect of CB2 agonists (JWH133 and GP1a) on the expression of CCR5 or CXCR4 receptors in MDM. Whether CB2 activation can attenuate HIV replication in vivo system is not known. In a simian immunodeficient virus (SIV) study, chronic delta 9 THC (partial CB1/CB2 agonist) administration attenuated plasma and cerebrospinal fluid (CSF) viral load in the infected animals and in vitro THC decreased SIV replication in human T cell line MT4-R5 cells (Molina et al. 2011). These authors did not examine whether the effect was mediated through CB1 or CB2 receptor. In a randomized placebo-controlled clinical trial in HIV-infected patients, short- term marijuana exposure (21 days) was associated with a reduction in viral load (Abrams et al. 2003). The role of CB2 receptors cannot be ascertained from this study since marijuana exposure is expected to activate both CB1 and CB2 receptors. Whether CB2 agonists can inhibit HIV replication in humans is not known. In vitro studies discussed above suggest that CB2 agonists can inhibit HIV replication in macrophages and microglia. Thus, CB2 activation has potential to further reduce or eliminate HIV replication in the brain of HIVinfected patients who are on HAART. Further studies are required to determine the role of CB2e receptor activation in HIV replication in vivo system.
CB2 and Inflammation CB2 receptor activation has been shown to reduce inflammatory responses in various cells types, particularly those of immune system (Pini et al. 2012). Gorantla et al. (2010) evaluated the role of CB2 receptor activation in the attenuation of HIV-induced brain inflammation using a murine model of neuroAIDS. In this model, encephalitis is produced in mice by injecting HIV-1-infected human MDM into the brain of immunodeficient mice reconstituted with human peripheral blood lymphocytes (hu-PBL/HIVE). The encephalitis is characterized by increased infiltration of human cells (HLA-DQ expression) into mouse brain, increased microglial activation as shown by increased expression of Mac-1 (CD11b), and increased expression of inflammatory cytokine tumor necrosis factor-α (TNFα). Treatment with a selective CB2 receptor agonist, Gp1a, significantly reduced expression of HLA-DQ, Mac-1, and TNFα. Suppression of microglial activation and reduced TNFα production by CB2 receptor activation has also been reported by other investigators (Ehrhart et al. 2005; Facchinetti et al. 2003; Puffenbarger et al. 2000). CB2 receptor agonists may suppress leukocyte trafficking through BBB by reducing rolling and infiltration into inflamed areas (Xu et al. 2007) and/or by reducing the expression of endothelial cell adhesion molecules required for transmigration (Burstein et al. 1992; Mestre et al. 2009). Since inflammation is primarily responsible for HIV-1associated neuronal damage, CB2 agonist treatment has potential to down regulate inflammatory changes that may attenuate HAND.
potent chemoattractant for monocytes (Mitola et al. 1997; Albini et al. 1998). Because of these properties, Tat has been implicated in HIV neuro pathogenesis. Fraga et al. (2011) investigated the role of delta-9 tetrahydrocannabinol (THC) and CP55940 (dual cannabinoid agonist for CB1 and CB2 receptors) in the migration of mouse BV-2 microglial cells towards Tat. Both cannabinoids significantly inhibited the migration of BV-2 cells towards Tat. A similar inhibitory response was obtained when the endogenous cannabinoid 2-arachidonoylglycerol was used. The inhibition of Tat migration was blocked by the CB2 receptor antagonist SR144528, but not by the CB1 receptor antagonist SR141716A. Similarly, CB2 receptor knockdown with small interfering RNA reversed the cannabinoid-mediated inhibition. In a similar study, THC and CP55940 were shown to significantly inhibit migration of human U937 macrophage-like cells to the Tat protein in a concentration-related manner (Raborn and Cabral 2010). Using selective CB1 and CB2 receptor agonists and antagonists, these researchers showed that the inhibitory effect of cannabinoid on the macrophage migration to Tat was mediated via CB2 receptor activation. In addition, the level of the β-chemokine receptor CCR-3 was reduced and its intracellular compartmentation was altered. These results indicate that cannabinoid-mediated inhibition of BV-2 microglial-like or macrophage-like cell migration to Tat is mediated through CB2 receptor activation. Therefore, CB2 may attenuate HAND by down-regulating neuroinflammation by blocking chemokine-like activity of Tat.
CB2 and BBB Integrity CB2 and Chemokine-Like Activity of Tat Chemokines play an important role in the initiation of inflammatory process by triggering the migration of inflammatory leukocytes from the peripheral circulation into various organs. HIV-1 Tat (trans-activating factor) is a regulatory protein that exhibits beta chemokine-like activity (Albini et al. 1998; de Paulis et al. 2000) and it has been shown to displace binding of beta chemokines from the beta chemokine receptors CCR2 and CCR3 (Albini et al. 1998). Tat is highly immunogenic and induces the production of proinflammatory cytokines and chemokines in astrocytes (El-Hage et al. 2006), monocytes (Lafrenie et al. 1997), microglia (Minghetti et al. 2004), and T lymphocytes (Kim et al. 2004). Tat-activated monocytes upregulate cell surface adhesion molecules, including vascular cell adhesion molecule-1 and intercellular adhesion molecule1 (Pu et al. 2003). In addition, it has been reported that Tat is a
The BBB is a dynamic interphase between the peripheral circulation and the central nervous system (CNS) and it is composed of microvascular endothelium, astrocytes, and pericytes. Impairment of BBB integrity has been linked to various inflammatory brain diseases such as Alzheimer, multiple sclerosis (Persidsky et al. 2006), and it plays an important role in the pathogenesis of HAND where inflammatory mediators are primarily responsible for the breakdown of BBB integrity (Avison et al. 2004). While investigating the role of CB2 receptors in the attenuation of TNFα-induced changes in coronary artery endothelial cells, Rajesh et al. (2007) discovered that activation of CB2 receptors by CB2 agonist JWH 133 or HU 308 attenuated TNFα-induced transendothelial migration of monocytes, which could partially be attributed to the restoration of the integrity of endothelial cell junctions. Subsequently, Ramirez et al. (2012) investigated the role of CB2 activation on BBB integrity under inflammatory
conditions using a mouse model of lipopolysaccharide (LPS)induced encephalitis. In this study, CB2 agonists (JWH133, and O-1966) prevented LPS-induced barrier leakiness and this was associated with an increase in transendothelial electrical resistance and tight junction proteins. These results suggest that CB2 activation may protect BBB integrity from neuroinflammation and thereby attenuate HAND. Interestingly, Lu et al. (2008) did not observe significant effect of CB2 activation on BBB permeability. This discrepancy could be due to the fact that these researchers investigated the effects of cannabinoid receptor activation under noninflammatory condition where CB1, but not CB2, activation was shown to decrease gp120-induced increased BBB permeability by up-regulating the expression of tight junction proteins.
CB2 and Dendritic/Synapse Injury HIV-1 infection of the CNS results in dendritic pruning and a reduction in spine density and these changes are correlated with cognitive impairment in AIDS patients (Sa et al. 2004). GP120 produces dendritic pruning and loss of spines when applied to neurons in culture or expressed in transgenic animals (Toggas et al. 1994; Viviani et al. 2006). In addition, Tat has been shown to induce synapse loss between hippocampal neurons in culture (Kim et al. 2008a) and impair synapse function when expressed in transgenic mice (Fitting et al. 2013). Since cannabinoid receptor agonists prevented or even reversed synapse loss induced by intense excitatory synaptic activity (Kim et al. 2008b), these researchers investigated whether cannabinoids can prevent synapse loss between cultured hippocampal neurons induced by HIV proteins Tat and gp120 (Kim et al. 2011). In this study, morphology and synapses between cultured hippocampal neurons were visualized by confocal imaging of neurons expressing DsRed2 and postsynaptic density protein 95 fused to green fluorescent protein (PSD95-GFP). The synaptic network that forms between hippocampal neurons in culture was significantly degraded after exposure to the HIV envelope protein gp120 for 24 h and the synapse loss preceded neuronal cell death. Mechanistic studies revealed that sequential activation of CXCR4, the interleukin-1β (IL-1β) receptor, the N-methylD-aspartate receptor, and ubiquitin ligase was required for the gp120-induced synapse loss. The cannabinoid full agonist Win55,212,2 inhibited gp120-induced, but not Tat-induced, synapse loss. This can be reversed by CB2 receptors antagonist, suggesting that the effect of cannabinoid is mediated via CB2 receptor activation. These results indicate that CB2 receptor agonist has potential to attenuate or reverse the
cognitive decline in HAND patients by preventing gp120induced loss of synapse.
CB2 and Cocaine Addiction Cocaine use is a risk factor for HIV infection and it contributes to the progression of AIDS (Fiala et al. 1998; Larrat and Zierler 1993; Webber et al. 1999). Similar to HIV infection, cocaine use/addiction can also lead to the development of neurocognitive disorders (Beatty et al. 1995; Ardila et al. 1991; Rosselli et al. 2001; Verdejo-Garcia and Perez-Garcia 2007). Furthermore, cocaine use has been shown to exacerbate neurocognitive impairment in HIV patients (Levine et al. 2006; Meade et al. 2011). Therefore, in cocaine-abusing HIV patients, attenuation of cocaine addiction may help reduce the severity of HAND. Interestingly, CB2 receptor activation has been shown to attenuate cocaine addiction in experimental animals (Xi et al. 2011; Aracil-Fernandez et al. (2012). Xi et al. (2011) reported that systemic, intranasal or intra-accumbens administration of JWH133 (a selective CB2 receptor agonist) inhibits intravenous cocaine self-administration, and attenuates cocaine-enhanced accumbens dopamine in wild-type and CB1 receptor-knockout (CB1−/−), but not in CB2−/−, mice. In addition, Intra-accumbens JWH133 alone decreased, while intra-accumbens AM630 (a selective CB2 antagonist) elevated, extracellular dopamine in wild type and CB1−/−mice, but not in CB2−/−mice. Intra-accumbens AM630 also blocked the reduction in cocaine selfadministration and extracellular dopamine produced by systemic administration of JWH133. Similar findings were reported by Aracil-Fernandez et al. (2012) in that cocaine intravenous self-administration was significantly less in CB2 overexpressing mice when compared to wild type mice. Importantly, CB2 overexpressing mice exhibited cocaine-induced conditioned place aversion. Moreover, they detected the presence of CB2 receptors in neurons and astrocytes which were colocalized with D2 dopamine receptors in the ventral tegmental area and nucleus accumbens. These findings suggest that brain CB2 receptors modulate cocaine’s rewarding effects, which appears to be dopamine-dependent. Since CB2 receptor activation has been shown to attenuate some of the pathological features that underlie the development of HAND, and reduce cocaine self-administration in experimental animals, treatment with CB2 agonist may have potential to treat HAND directly as well as indirectly by attenuating cocaine addiction.
Fig. 1 CB2 activation may attenuate HAND by inhibiting HIV replication, down regulating inflammation, inhibiting chemokine-like activity of Tat, and preventing synapse loss. Inhibited HIV replication can attenuate neuronal injury by decreasing the production of neurotoxic HIV proteins, Tat and HIV-1gp120. Down regulation of inflammation is mediated through blunted activation of macrophage/ microglia; decreased production of TNFα, chemokines, and adhesion molecules; and reduced chemokine-like activity of Tat. Down regulated inflammation can decrease BBB permeability and leukocyte infiltration resulting in reduced neuronal injury
Role of CB2 Receptor Activation in the Attenuation of HAND CB2 Activation
HIV replication (macrophage/ Microglia/ CD4 +T cells)
Macrophage/ microglia activation
Chemokine-like Tat activity
Synapse loss
TNF /chemokine/ adhesion molecule
Tat and gp120 Inflammation BBB permeability Leukocyte infiltration Neuronal injury
HAND
Summary
References
A summary of the role of CB2 activation has been presented in Fig. 1. CB2 receptor activation can attenuate HAND severity by inhibiting HIV replication, blunting HIV-triggered neuroinflammation, preventing HIV-induced damage to BBB integrity, and preventing HIV-associated synapse loss. CB2 receptor activation may inhibit HIV replication in peri vascular macrophages, microglia, and CD4+ T cells. This is expected to decrease the production of neurotoxic HIV products. CB2 receptor activation can disrupt HIV-triggered inflammatory cascade including down regulating activation of brain innate immunity, inhibiting production of proinflammatory cytokines (for example, TNFα, IL-1β), blunting chemokine activity of Tat and other chemokines, down regulating the expression of adhesion molecules, and blocking brain transmigration of HIVinfected leukocytes. Blunting inflammation appears to be a mechanism whereby CB2 receptor activation prevents HIVinduced damage to BBB integrity. CB2 receptor activation may also minimize neuronal loss, and thus attenuate HAND, by blocking gp120-induced synapse loss directly and indirectly by reducing the production of Tat and gp120 via suppressing HIV replication. Finally, in cocaine-abusing HIV patients, attenuation of cocaine addiction by CB2 receptor activation may help reduce the clinical manifestations of HAND.
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Conflict of Interest Statement Authors declare no conflict of interest.
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