Full-length ArticleCCR5 mediates HIV-1 Tat-induced neuroinflammation and influences morphine tolerance, dependence, and reward
Introduction
There is a dynamic relationship between opioid use, human immunodeficiency virus-1 (HIV-1) acquisition, and disease progression. Worldwide, injection drug use (IDU) accounts for ∼30% of new HIV-1 infections outside of sub-Saharan Africa (WHO, 2016). Within the United States, over 3500 new infections involved IDU in 2015 (CDC, 2016), a year in which overall drug overdose deaths rose another 11%, the majority (63%) of which involved opioids (Rudd et al., 2016). The convergence of the HIV and opioid epidemics is particularly concerning given evidence that opioid usage increases the progression of HIV-1 to acquired immune deficiency syndrome (AIDS) and promotes neurocognitive impairment in humans and non-human primates (Bokhari et al., 2011, Bell et al., 1996, Bell et al., 2002, Bell et al., 2006, Chuang et al., 2005, Donahoe et al., 1993, Kumar et al., 2004, Kumar et al., 2006, Rivera et al., 2013). Moreover, HIV-infected individuals are at risk for the development of neuropathic pain (Malvar et al., 2015) for which prescription opioids remain a common treatment (Kremer et al., 2016, Zilliox, 2017). Pharmacological treatment for opioid abuse includes substitution therapies (Moatti et al., 1998, Roux et al., 2008, Sambamoorthi et al., 2000, Woody et al., 2014), which may exert neurotoxic interactions with HIV-1 proteins (Fitting et al., 2014b). As such, the mechanisms and physiological consequences of HIV/opioid interactions need to be understood in order to improve outcomes for HIV-seropositive patients that are pharmacologically managed for pain and/or addiction.
The biological mechanisms that underlie HIV-1 and opioid interactions in the central nervous system (CNS) likely involve the HIV-1 regulatory protein, trans-activator of transcription (Tat). Tat is critical for efficient HIV replication; however, Tat is soluble and can be secreted from infected cells to exert direct and indirect neurotoxicity in vitro (reviewed in King et al., 2006, Nath et al., 2002). Tat promotes neuroinflammation via NF-κB signaling (El-Hage et al., 2008b, Herbein et al., 2010), upregulation of pro-inflammatory cytokines [particularly the endogenous β-chemokine ligands for the C-C “motif” chemokine receptor type 5 (CCR5): C-C chemokine ligand 3 (CCL3, also known as “macrophage inflammatory protein-1α” or MIP-1α), CCL4 (also known as “macrophage inflammatory protein-1β” or MIP-1β), and CCL5 (also known as “regulated on activation normal T-cell expressed and secreted” or RANTES); El-Hage et al., 2005, Hahn et al., 2010], and subsequent recruitment of neuroimmune cells promoting neuroinflammation. In vitro, morphine exacerbates Tat effects to activate microglia (Bokhari et al., 2009, Gupta et al., 2010, Sorrell and Hauser, 2014), increase cytokine production (Bokhari et al., 2009, El-Hage et al., 2005, Fitting et al., 2014b, Turchan-Cholewo et al., 2009), drive oxidative stress (Dalvi et al., 2016, Fitting et al., 2014a, Fitting et al., 2014b, Malik et al., 2011, Turchan-Cholewo et al., 2009), increase intracellular calcium (El-Hage et al., 2005, Fitting et al., 2014a, Fitting et al., 2014b), and promote neurotoxicity (Fitting et al., 2014a, Fitting et al., 2014b, Gurwell et al., 2001, Malik et al., 2011). Morphine and Tat interactions may depend on µ opioid receptors (MORs) given that neurotoxic synergy is observed in co-cultures when mixed glia express MORs, but not when they are derived from MOR−/− mice (Zou et al., 2011). These data support the notion that glial MORs are critical for the interactive neurotoxic effects of combined morphine and Tat exposure.
The proinflammatory effects of HIV-1 Tat at CCR5 may directly influence opioid sensitivity. In studies of opioid-mediated antinociception in rats, activation of CCR5 or CXCR4 can rapidly (within 30 min) desensitize µ- or δ-opioid-receptors (Chen et al., 2007). Blocking actions at CCR5 in proinflammatory states may attenuate heterologous desensitization of MORs and increase therapeutic efficacy. In support, intrathecal administration of the CCR5 antagonist, maraviroc, attenuated chronic constriction injury-induced microgliosis, astrogliosis, upregulation of CCR5 protein, and mRNA expression of CCR5-ligands (CCL3, CCL4, and CCL5) in the spinal cord and dorsal root ganglion concurrent with reduced neuropathic pain (Kwiatkowski et al., 2016). Moreover, CCR5 and MORs may form functionally active heteromers. A bivalent ligand derived from a MOR agonist (oxymorphone) and a CCR5 antagonist (TAK-220) had ∼2000× greater antinociceptive potency than morphine in mice experiencing LPS-mediated inflammation (Akgün et al., 2015). Another bivalent ligand comprised of an opioid receptor antagonist (naltrexone) and maraviroc reduced the infectivity of human astrocytes when cultured with R5-tropic HIV (Arnatt et al., 2016, El-Hage et al., 2013, Yuan et al., 2013). These data suggest a dynamic relationship between MOR and CCR5 activation that may contribute to HIV pathology; however, the functional effects are poorly understood. As such, we investigated morphine tolerance, dependence, and reward in a transgenic murine model that conditionally-expresses the proinflammatory HIV-1 regulatory protein, Tat1–86. Using a transgenic mouse approach, conditional Tat expression has been demonstrated to reduce the antinociceptive potency of morphine (Fitting et al., 2012, Fitting et al., 2016), while potentiating psychostimulant reward in acute drug withdrawal (24 h post drug administration; Paris et al., 2014a, Paris et al., 2014b). We hypothesized that HIV-1 Tat expression would attenuate morphine antinociceptive potency and that the CCR5 antagonist, maraviroc, would reverse these effects. Further, we hypothesized that 24 h post morphine, Tat- and cytokine-mediated effects would be potentiated.
Section snippets
Materials and methods
The use of mice in these studies was pre-approved by the Institutional Animal Care and Use Committee at Virginia Commonwealth University and the experiments were conducted in accordance with ethical guidelines defined by the National Institutes of Health (NIH Publication No. 85-23).
HIV-1 Tat decreased morphine potency in non-tolerant mice; tolerance or pharmacological antagonism of CCR5 attenuated Tat effects
As negative control measures before proceeding to tests involving Tat-tg mice, morphine dosing, non-specific interactions with maraviroc, and warm-water tail-withdrawal test conditions were confirmed in C57BL/6J mice. In a 52 °C water bath, morphine administered at 5 mg/kg (Fig. 1A) or 10 mg/kg (Fig. 1B) produced antinociception that was present for at least 2 h and peaked at 60 min, commensurate with observations in other animal models (Altun et al., 2015, Williams et al., 2008). In a 56 °C
Discussion
The overall hypotheses that HIV-1 Tat expression attenuates morphine potency, CCR5 antagonism reverses these effects, and withholding morphine for 24 h exacerbates Tat’s effects on cytokines were upheld. The present data revealed even greater nuance in the behavioral response to morphine regimens than was anticipated. Consistent with prior reports (Fitting et al., 2012, Fitting et al., 2016), HIV-1 Tat expression significantly attenuated the antinociceptive potency of acute morphine injection
Conclusions
Several investigations using murine and human cell cultures have demonstrated neurotoxic interactions between HIV-1 Tat, MORs, and CCR5. The present findings extend these data by investigating functional consequences of such interactions on morphine-mediated antinociception, tolerance, and reward in a murine model. Maraviroc blocked Tat’s actions to attenuate the antinociceptive potency of acute morphine in non-tolerant mice. Intriguingly, maraviroc also potentiated the Tat-induced increase of
Acknowledgments
This work was supported by funds from NIH: T32 DA007027 (WLD), P30 DA033934 (WLD), R01 DA036975 (WLD and HIA), R01 DA034231 (PEK and KFH), K02 DA027374 (KFH), R01 DA018633 (KFH), R01 DA033200 (KFH), and R00 DA039791 (JJP). We thank Ms. Tamara Vujanovic for her assistance with figures.
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2023, Current Opinion in NeurobiologyCitation Excerpt :Reciprocally, HIV-1 Tat expression is also known to affect morphine's efficacy and potency in vivo, reducing it depending on the context [77–79]. Interactions with CCR5 clearly play a role in these outcomes since the CCR5 antagonist maraviroc can reinstate morphine's antinociceptive potency and restore physical dependence in morphine-tolerant mice exposed to HIV-1 Tat [80]. Both glia and neurons can express CCR5, raising the question of whether both cell types may participate, perhaps differently, in modulating the neurotoxic effects of MOR activation.
Persistent sensory changes and sex differences in transgenic mice conditionally expressing HIV-1 Tat regulatory protein
2022, Experimental NeurologyCitation Excerpt :An important limitation of our morphine and gabapentin results is the use of a single dose of these drugs. It is possible that a subchronic or chronic gabapentin regimen and/or periods of abstinence may elicit a divergent response, as has been observed for morphine (Gonek et al., 2018). Future work assessing dose-response curves may reveal shifts in the nociceptive profile of Tat mice.
Independent actions by HIV-1 Tat and morphine to increase recruitment of monocyte-derived macrophages into the brain in a region-specific manner
2022, Neuroscience LettersCitation Excerpt :This contrasts with other studies reporting that Tat exposure can increases chemokine levels. In intact rodent models and in astrocytes isolated from rodents, HIV-1 Tat increases CCL5, a chemokine ligand of CCR5, [36,87–90]. Other chemokines, such as CCL4 [87,88], CCL3 [87], CXCL1 [87,88] and CCL11 [87,88] are also elevated upon Tat exposure.