Elsevier

Brain, Behavior, and Immunity

Volume 69, March 2018, Pages 124-138
Brain, Behavior, and Immunity

Full-length Article
CCR5 mediates HIV-1 Tat-induced neuroinflammation and influences morphine tolerance, dependence, and reward

https://doi.org/10.1016/j.bbi.2017.11.006Get rights and content

Highlights

  • HIV Tat decreases morphine potency and CCR5 antagonism attenuates Tat effects.

  • Tat decreases morphine withdrawal and CCR5 antagonism attenuates Tat effects.

  • Tat exposure and CCR5 antagonism attenuate the psychomotor response to morphine.

  • CCR5 antagonism potentiated Tat-promoted morphine conditioned place preference.

  • 24 h post drug, Tat elevates central cytokines; CCR5 blockade attenuates Tat effects.

Abstract

The HIV-1 regulatory protein, trans-activator of transcription (Tat), interacts with opioids to potentiate neuroinflammation and neurodegeneration within the CNS. These effects may involve the C-C chemokine receptor type 5 (CCR5); however, the behavioral contribution of CCR5 on Tat/opioid interactions is not known. Using a transgenic murine model that expresses HIV-1 Tat protein in a GFAP-regulated, doxycycline-inducible manner, we assessed morphine tolerance, dependence, and reward. To assess the influence of CCR5 on these effects, mice were pretreated with oral vehicle or the CCR5 antagonist, maraviroc, prior to morphine administration. We found that HIV-1 Tat expression significantly attenuated the antinociceptive potency of acute morphine (2–64 mg/kg, i.p.) in non-tolerant mice. Consistent with this, Tat attenuated withdrawal symptoms among morphine-tolerant mice. Pretreatment with maraviroc blocked the effects of Tat, reinstating morphine potency in non-tolerant mice and restoring withdrawal symptomology in morphine-tolerant mice. Twenty-four hours following morphine administration, HIV-1 Tat significantly potentiated (∼3.5-fold) morphine-conditioned place preference and maraviroc further potentiated these effects (∼5.7-fold). Maraviroc exerted no measurable behavioral effects on its own. Protein array analyses revealed only minor changes to cytokine profiles when morphine was administered acutely or repeatedly; however, 24 h post morphine administration, the expression of several cytokines was greatly increased, including endogenous CCR5 chemokine ligands (CCL3, CCL4, and CCL5), as well as CCL2. Tat further elevated levels of several cytokines and maraviroc pretreatment attenuated these effects. These data demonstrate that CCR5 mediates key aspects of HIV-1 Tat-induced alterations in the antinociceptive potency and rewarding properties of opioids.

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.

References (116)

  • S. Fitting et al.

    Morphine efficacy is altered in conditional HIV-1 Tat transgenic mice

    Eur. J. Pharmacol.

    (2012)
  • J.A. Foster et al.

    Gut-brain axis: how the microbiome influences anxiety and depression

    Trends Neurosci.

    (2013)
  • S. Gupta et al.

    HIV-Tat elicits microglial glutamate release: role of NAPDH oxidase and the cystine-glutamate antiporter

    Neurosci. Lett.

    (2010)
  • J.A. Gurwell et al.

    Synergistic neurotoxicity of opioids and human immunodeficiency virus-1 Tat protein in striatal neurons in vitro

    Neuroscience

    (2001)
  • L.W. Hutson et al.

    Interleukin-1 signaling in the basolateral amygdala is necessary for heroin-conditioned immunosuppression

    Brain Behav. Immun.

    (2017)
  • J.E. King et al.

    HIV tat and neurotoxicity

    Microbes Infect.

    (2006)
  • M. Kremer et al.

    Antidepressants and gabapentinoids in neuropathic pain: mechanistic insights

    Neuroscience

    (2016)
  • R. Kumar et al.

    Chronic morphine exposure causes pronounced virus replication in cerebral compartment and accelerated onset of AIDS in SIV/SHIV-infected Indian rhesus macaques

    Virology

    (2006)
  • K. Kwiatkowski et al.

    Beneficial properties of maraviroc on neuropathic pain development and opioid effectiveness in rats

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2016)
  • C.R. Leibrand et al.

    HIV-1 Tat disrupts blood-brain barrier integrity and increases phagocytic perivascular macrophages and microglia in the dorsal striatum of transgenic mice

    Neurosci. Lett.

    (2017)
  • S.D. Mahajan et al.

    Morphine modulates chemokine gene regulation in normal human astrocytes

    Clin. Immunol.

    (2005)
  • T. Miyagi et al.

    Morphine induces gene expression of CCR5 in human CEMx174 lymphocytes

    J. Biol. Chem.

    (2000)
  • J.J. Paris et al.

    Central administration of angiotensin IV rapidly enhances novel object recognition among mice

    Neuropharmacology

    (2013)
  • J.J. Paris et al.

    Exposure to HIV-1 Tat in brain impairs sensorimotor gating and activates microglia in limbic and extralimbic brain regions of male mice

    Behav. Brain Res.

    (2015)
  • R.T. Rahim et al.

    Paradoxes of immunosuppression in mouse models of withdrawal

    J. Neuroimmunol.

    (2004)
  • R.T. Rahim et al.

    Withdrawal from morphine in mice suppresses splenic macrophage function, cytokine production, and costimulatory molecules

    J. Neuroimmunol.

    (2003)
  • I. Rivera et al.

    Identification and molecular characterization of SIV Vpr R50G mutation associated with long term survival in SIV-infected morphine dependent and control macaques

    Virology

    (2013)
  • U. Sambamoorthi et al.

    Drug abuse, methadone treatment, and health services use among injection drug users with AIDS

    Drug Alcohol Depend.

    (2000)
  • T.B. Saurer et al.

    Neuroimmune mechanisms of opioid-mediated conditioned immunomodulation

    Brain Behav. Immun.

    (2008)
  • S. Semenova et al.

    Strain differences in the analgesic and reinforcing action of morphine in mice

    Pharmacol. Biochem. Behav.

    (1995)
  • T.S. Shippenberg et al.

    Delta-opioid receptor antagonists prevent sensitization to the conditioned rewarding effects of morphine

    Biol. Psychiatry

    (2009)
  • C. Song et al.

    Protein kinase Czeta mediates micro-opioid receptor-induced cross-desensitization of chemokine receptor CCR5

    J. Biol. Chem.

    (2011)
  • A.D. Steele et al.

    Mu-opioid modulation of HIV-1 coreceptor expression and HIV-1 replication

    Virology

    (2003)
  • E. Akgün et al.

    Inhibition of inflammatory and neuropathic pain by targeting a mu opioid receptor/chemokine receptor5 heteromer (MOR-CCR5)

    J. Med. Chem.

    (2015)
  • A. Altun et al.

    The effects of endocannabinoid receptor agonist anandamide and antagonist rimonabant on opioid analgesia and tolerance in rats

    Gen. Physiol. Biophys.

    (2015)
  • E. Angelakis et al.

    Abnormal weight gain and gut microbiota modifications are side effects of long-term doxycycline and hydroxychloroquine treatment

    Antimicrob. Agents Chemother.

    (2014)
  • V. Avdoshina et al.

    Morphine induces the release of CCL5 from astrocytes: potential neuroprotective mechanism against the HIV protein gp120

    Glia

    (2010)
  • J.E. Bell et al.

    Neurobiology of multiple insults: HIV-1-associated brain disorders in those who use illicit drugs

    J Neuroimmune Pharmacol.

    (2006)
  • J.E. Bell et al.

    HIV and drug misuse in the Edinburgh cohort

    J. Acquir. Immune Defic. Syndr.

    (2002)
  • J.E. Bell et al.

    Influence of risk group and zidovudine therapy on the development of HIV encephalitis and cognitive impairment in AIDS patients

    AIDS

    (1996)
  • J.W. Berman et al.

    NeuroAIDS, drug abuse, and inflammation: building collaborative research activities

    J. Neuroimmune Pharmacol.

    (2006)
  • S.M. Bokhari et al.

    Morphine potentiates neuropathogenesis of SIV infection in rhesus macaques

    J. Neuroimmune Pharmacol.

    (2011)
  • S.M. Bokhari et al.

    Morphine enhances Tat-induced activation in murine microglia

    J. Neurovirol.

    (2009)
  • A.J. Bruce-Keller et al.

    Morphine causes rapid increases in glial activation and neuronal injury in the striatum of inducible HIV-1 Tat transgenic mice

    Glia

    (2008)
  • J.M. Cavaillon et al.

    Bench-to-bedside review: endotoxin tolerance as a model of leukocyte reprogramming in sepsis

    Crit. Care

    (2006)
  • Centers for Disease Control and Prevention, 2016. HIV Surveillance Report, 2015; vol. 27....
  • R.Y. Chuang et al.

    Opioids and the progression of simian AIDS

    Front Biosci.

    (2005)
  • J.F. Cryan et al.

    Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour

    Nat. Rev. Neurosci.

    (2012)
  • P. Dalvi et al.

    Enhanced autophagy in pulmonary endothelial cells on exposure to HIV-Tat and morphine: role in HIV-related pulmonary arterial hypertension

    Autophagy

    (2016)
  • R.M. Donahoe et al.

    Consequences of opiate-dependency in a monkey model of AIDS

    Adv. Exp. Med. Biol.

    (1993)
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