Abstract
Despite the ability of combination antiretroviral therapy to dramatically suppress viremia, the brain continues to be a reservoir of HIV-1 low-level replication. Adding further complexity to this is the comorbidity of drug abuse with HIV-1 associated neurocognitive disorders and neuroHIV. Among several abused drugs, the use of opiates is highly prevalent in HIV-1 infected individuals, both as an abused drug as well as for pain management. Opioids and their receptors have attained notable attention owing to their ability to modulate immune functions, in turn, impacting disease progression. Various cell culture, animal and human studies have implicated the role of opioids and their receptors in modulating viral replication and virus-mediated pathology both positively and negatively. Further, the combinatorial effects of HIV-1/HIV-1 proteins and morphine have demonstrated activation of inflammatory signaling in the host system. Herein, we summarized the current knowledge on the role of opioids on peripheral immunopathogenesis, viral immunopathogenesis, epigenetic profiles of the host and viral genome, neuropathogenesis of SIV/SHIV-infected non-human primates, blood-brain-barrier, HIV-1 viral latency, and viral rebound. Overall, this review provides recent insights into the role of opioids in HIV-1 immunopathogenesis.
Similar content being viewed by others
References
Altice FL, Bruce RD, Lucas GM, Lum PJ, Korthuis PT, Flanigan TP, Cunningham CO, Sullivan LE, Vergara-Rodriguez P, Fiellin DA, Ca**a A, Botsko M, Nandi V, Gourevitch MN, Finkelstein R, BHIVES Collaborative (2011) HIV treatment outcomes among HIV-infected, opioid-dependent patients receiving buprenorphine/naloxone treatment within HIV clinical care settings: results from a multisite study. J Acquir Immune Defic Syndr 56(Suppl 1):S22–S32. https://doi.org/10.1097/QAI.0b013e318209751e
Anderson CE et al (2003) Relationship of Nef-positive and GFAP-reactive astrocytes to drug use in early and late HIV infection. Neuropathol Appl Neurobiol 29:378–388. https://doi.org/10.1046/j.1365-2990.2003.00475.x
Atluri VS (2016) Editorial: HIV and Illicit Drugs of Abuse. Front Microbiol 7:221. https://doi.org/10.3389/fmicb.2016.00221
Baba M, Oishi R, Saeki K (1988) Enhancement of blood-brain barrier permeability to sodium fluorescein by stimulation of mu opioid receptors in mice. Naunyn Schmiedebergs Arch Pharmacol 337:423–428. https://doi.org/10.1007/bf00169534
Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392:245–252. https://doi.org/10.1038/32588
Banerjee A, Strazza M, Wigdahl B, Pirrone V, Meucci O, Nonnemacher MR (2011) Role of mu-opioids as cofactors in human immunodeficiency virus type 1 disease progression and neuropathogenesis. J Neurovirol 17:291–302. https://doi.org/10.1007/s13365-011-0037-2
Basu S, Bruce RD, Barry DT, Altice FL (2007) Pharmacological pain control for human immunodeficiency virus-infected adults with a history of drug dependence. J Subst Abus Treat 32:399–409. https://doi.org/10.1016/j.jsat.2006.10.005
Bhargava HN, Thomas PT, Thorat S, House RV (1994) Effects of morphine tolerance and abstinence on cellular immune function. Brain Res 642:1–10. https://doi.org/10.1016/0006-8993(94)90899-0
Bokhari SM, Hegde R, Callen S, Yao H, Adany I, Li Q, Li Z, Pinson D, Yeh HW, Cheney PD, Buch S (2011) Morphine potentiates neuropathogenesis of SIV infection in rhesus macaques. J NeuroImmune Pharmacol 6:626–639. https://doi.org/10.1007/s11481-011-9272-9
Borman A, Ciepielewski Z, Wrona D, Stojek W, Glac W, Leszkowicz E, Tokarski J (2009) Small doses of morphine can enhance NK cell cytotoxicity in pigs. Int Immunopharmacol 9:277–283. https://doi.org/10.1016/j.intimp.2008.11.006
Borner C et al (2009) Mechanisms of opioid-mediated inhibition of human T cell receptor signaling. J Immunol 183:882–889. https://doi.org/10.4049/jimmunol.0802763
Borner C, Lanciotti S, Koch T, Hollt V, Kraus J (2013) Mu opioid receptor agonist-selective regulation of interleukin-4 in T lymphocytes. J Neuroimmunol 263:35–42. https://doi.org/10.1016/j.jneuroim.2013.07.012
Bouwman FH et al (1998) Variable progression of HIV-associated dementia. Neurology 50:1814–1820. https://doi.org/10.1212/wnl.50.6.1814
Breslow JM, Monroy MA, Daly JM, Meissler JJ, Gaughan J, Adler MW, Eisenstein TK (2011) Morphine, but not trauma, sensitizes to systemic Acinetobacter baumannii infection. J Neuroimmune Pharmacol 6:551–565. https://doi.org/10.1007/s11481-011-9303-6
Brown JN et al (2012) Morphine produces immunosuppressive effects in nonhuman primates at the proteomic and cellular levels. Mol Cell Proteomics 11:605–618. https://doi.org/10.1074/mcp.M111.016121
Bushman F, Lewinski M, Ciuffi A, Barr S, Leipzig J, Hannenhalli S, Hoffmann C (2005) Genome-wide analysis of retroviral DNA integration. Nat Rev Microbiol 3:848–858. https://doi.org/10.1038/nrmicro1263
Bussiere JL, Adler MW, Rogers TJ, Eisenstein TK (1992) Differential effects of morphine and naltrexone on the antibody response in various mouse strains. Immunopharmacol Immunotoxicol 14:657–673. https://doi.org/10.3109/08923979209005416
Bussiere JL, Adler MW, Rogers TJ, Eisenstein TK (1993) Cytokine reversal of morphine-induced suppression of the antibody response. J Pharmacol Exp Ther 264:591–597
Byrd DA et al (2011) Neurocognitive impact of substance use in HIV infection. J Acquir Immune Defic Syndr 58:154–162. https://doi.org/10.1097/QAI.0b013e318229ba41
Cai Y, Yang L, Hu G, Chen X, Niu F, Yuan L, Liu H, **ong H, Arikkath J, Buch S (2016) Regulation of morphine-induced synaptic alterations: role of oxidative stress, ER stress, and autophagy. J Cell Biol 215:245–258. https://doi.org/10.1083/jcb.201605065
Carr DJ, Mayo S, Gebhardt BM, Porter J (1994) Central alpha-adrenergic involvement in morphine-mediated suppression of splenic natural killer activity. J Neuroimmunol 53:53–63. https://doi.org/10.1016/0165-5728(94)90064-7
Carr DJ, Rogers TJ, Weber RJ (1996) The relevance of opioids and opioid receptors on immunocompetence and immune homeostasis. Proc Soc Exp Biol Med 213:248–257. https://doi.org/10.3181/00379727-213-44056
Chandel N, Malhotra A, Singhal PC (2015) Vitamin D receptor and epigenetics in HIV infection and drug abuse. Front Microbiol 6:788. https://doi.org/10.3389/fmicb.2015.00788
Chang SL, Connaghan KP (2012) Behavioral and molecular evidence for a feedback interaction between morphine and HIV-1 viral proteins. J Neuroimmune Pharmacol 7:332–340. https://doi.org/10.1007/s11481-011-9324-1
Chang MC et al (2016) Anti-CD40 antibody and toll-like receptor 3 ligand restore dendritic cell-mediated anti-tumor immunity suppressed by morphine. Am J Cancer Res 6:157–172
Chaves C, Remiao F, Cisternino S, Decleves X (2017) Opioids and the Blood-Brain Barrier: A Dynamic Interaction with Consequences on Drug Disposition in Brain. Curr Neuropharmacol 15:1156–1173. https://doi.org/10.2174/1570159X15666170504095823
Chen K, Phan T, Lin A, Sardo L, Mele AR, Nonnemacher MR, Klase Z (2020) Morphine exposure exacerbates HIV-1 tat driven changes to neuroinflammatory factors in cultured astrocytes. PLoS One 15:e0230563. https://doi.org/10.1371/journal.pone.0230563
Chivero ET, Guo ML, Periyasamy P, Liao K, Callen SE, Buch S (2017) HIV-1 tat primes and activates microglial NLRP3 Inflammasome-mediated Neuroinflammation. J Neurosci 37:3599–3609. https://doi.org/10.1523/JNEUROSCI.3045-16.2017
Chuang LF, Killam KF Jr, Chuang RY (1993) Increased replication of simian immunodeficiency virus in CEM x174 cells by morphine sulfate. Biochem Biophys Res Commun 195:1165–1173. https://doi.org/10.1006/bbrc.1993.2167
Clark JD, Shi X, Li X, Qiao Y, Liang D, Angst MS, Yeomans DC (2007) Morphine reduces local cytokine expression and neutrophil infiltration after incision. Mol Pain 3:28. https://doi.org/10.1186/1744-8069-3-28
Cornwell WD, Wagner W, Lewis MG, Fan X, Rappaport J, Rogers TJ (2016) Effect of chronic morphine administration on circulating dendritic cells in SIV-infected rhesus macaques. J Neuroimmunol 295-296:30–40. https://doi.org/10.1016/j.jneuroim.2016.04.007
Dalvi P et al (2016) Enhanced autophagy in pulmonary endothelial cells on exposure to HIV-tat and morphine: role in HIV-related pulmonary arterial hypertension. Autophagy 12:2420–2438. https://doi.org/10.1080/15548627.2016.1238551
Das S, Kelschenbach J, Charboneau R, Barke RA, Roy S (2011) Morphine withdrawal stress modulates lipopolysaccharide-induced interleukin 12 p40 (IL-12p40) expression by activating extracellular signal-regulated kinase 1/2, which is further potentiated by glucocorticoids. J Biol Chem 286:29806–29817. https://doi.org/10.1074/jbc.M111.271460
Dauchy S et al (2008) ABC transporters, cytochromes P450 and their main transcription factors: expression at the human blood-brain barrier. J Neurochem 107:1518–1528. https://doi.org/10.1111/j.1471-4159.2008.05720.x
Dave RS (2012) Morphine affects HIV-induced inflammatory response without influencing viral replication in human monocyte-derived macrophages FEMS. Immunol Med Microbiol 64:228–236. https://doi.org/10.1111/j.1574-695X.2011.00894.x
Desplats P et al (2014) Epigenetic alterations in the brain associated with HIV-1 infection and methamphetamine dependence. PLoS One 9:e102555. https://doi.org/10.1371/journal.pone.0102555
Donahoe RM (2004) Multiple ways that drug abuse might influence AIDS progression: clues from a monkey model. J Neuroimmunol 147:28–32. https://doi.org/10.1016/j.jneuroim.2003.10.011
Dutta R, Roy S (2012) Mechanism(s) involved in opioid drug abuse modulation of HAND. Curr HIV Res 10:469–477. https://doi.org/10.2174/157016212802138805
Dutta R et al (2012) Morphine modulation of toll-like receptors in microglial cells potentiates neuropathogenesis in a HIV-1 model of coinfection with pneumococcal pneumoniae. J Neurosci 32:9917–9930. https://doi.org/10.1523/JNEUROSCI.0870-12.2012
El-Hage N, Gurwell JA, Singh IN, Knapp PE, Nath A, Hauser KF (2005) Synergistic increases in intracellular Ca2+, and the release of MCP-1, RANTES, and IL-6 by astrocytes treated with opiates and HIV-1. Tat Glia 50:91–106. https://doi.org/10.1002/glia.20148
El-Hage N, Wu G, Ambati J, Bruce-Keller AJ, Knapp PE, Hauser KF (2006a) CCR2 mediates increases in glial activation caused by exposure to HIV-1 tat and opiates. J Neuroimmunol 178:9–16. https://doi.org/10.1016/j.jneuroim.2006.05.027
El-Hage N et al (2006b) HIV-1 tat and opiate-induced changes in astrocytes promote chemotaxis of microglia through the expression of MCP-1 and alternative chemokines. Glia 53:132–146. https://doi.org/10.1002/glia.20262
El-Hage N, Bruce-Keller AJ, Yakovleva T, Bazov I, Bakalkin G, Knapp PE, Hauser KF (2008) Morphine exacerbates HIV-1 tat-induced cytokine production in astrocytes through convergent effects on [Ca(2+)](i), NF-kappaB trafficking and transcription. PLoS One 3:e4093. https://doi.org/10.1371/journal.pone.0004093
El-Hage N, Dever SM, Podhaizer EM, Arnatt CK, Zhang Y, Hauser KF (2013) A novel bivalent HIV-1 entry inhibitor reveals fundamental differences in CCR5-mu-opioid receptor interactions between human astroglia and microglia. AIDS 27:2181–2190. https://doi.org/10.1097/QAD.0b013e3283639804
El-Hage N, Rodriguez M, Dever SM, Masvekar RR, Gewirtz DA, Shacka JJ (2015) HIV-1 and morphine regulation of autophagy in microglia: limited interactions in the context of HIV-1 infection and opioid abuse. J Virol 89:1024–1035. https://doi.org/10.1128/JVI.02022-14
Fecho K, Maslonek KA, Coussons-Read ME, Dykstra LA, Lysle DT (1994) Macrophage-derived nitric oxide is involved in the depressed concanavalin A responsiveness of splenic lymphocytes from rats administered morphine in vivo. J Immunol 152:5845–5852
Felten SY, Olschowka J (1987) Noradrenergic sympathetic innervation of the spleen: II. Tyrosine hydroxylase (TH)-positive nerve terminals form synapticlike contacts on lymphocytes in the splenic white pulp. J Neurosci Res 18:37–48. https://doi.org/10.1002/jnr.490180108
Fiellin DA et al (2011) Drug treatment outcomes among HIV-infected opioid-dependent patients receiving buprenorphine/naloxone. J Acquir Immune Defic Syndr 56(Suppl 1):S33–S38. https://doi.org/10.1097/QAI.0b013e3182097537
Fitting S, Knapp PE, Zou S, Marks WD, Bowers MS, Akbarali HI, Hauser KF (2014) Interactive HIV-1 tat and morphine-induced synaptodendritic injury is triggered through focal disruptions in Na(+) influx, mitochondrial instability, and Ca(2)(+) overload. J Neurosci 34:12850–12864. https://doi.org/10.1523/JNEUROSCI.5351-13.2014
Glattard E, Welters ID, Lavaux T, Muller AH, Laux A, Zhang D, Schmidt AR, Delalande F, Laventie BJ, Dirrig-Grosch S, Colin DA, van Dorsselaer A, Aunis D, Metz-Boutigue MH, Schneider F, Goumon Y (2010) Endogenous morphine levels are increased in sepsis: a partial implication of neutrophils. PLoS One 5:e8791. https://doi.org/10.1371/journal.pone.0008791
Godai K et al (2014) Peripheral administration of morphine attenuates postincisional pain by regulating macrophage polarization through COX-2-dependent pathway. Mol Pain 10:36. https://doi.org/10.1186/1744-8069-10-36
Gonek M et al (2018) CCR5 mediates HIV-1 tat-induced neuroinflammation and influences morphine tolerance, dependence, and reward. Brain Behav Immun 69:124–138. https://doi.org/10.1016/j.bbi.2017.11.006
Grace PM et al (2014) Activation of adult rat CNS endothelial cells by opioid-induced toll-like receptor 4 (TLR4) signaling induces proinflammatory, biochemical, morphological, and behavioral sequelae. Neuroscience 280:299–317. https://doi.org/10.1016/j.neuroscience.2014.09.020
Greeneltch KM, Kelly-Welch AE, Shi Y, Keegan AD (2005) Chronic morphine treatment promotes specific Th2 cytokine production by murine T cells in vitro via a Fas/Fas ligand-dependent mechanism. J Immunol 175:4999–5005. https://doi.org/10.4049/jimmunol.175.8.4999
Grimm MC, Ben-Baruch A, Taub DD, Howard OM, Wang JM, Oppenheim JJ (1998) Opiate inhibition of chemokine-induced chemotaxis. Ann N Y Acad Sci 840:9–20. https://doi.org/10.1111/j.1749-6632.1998.tb09544.x
Guo CJ, Li Y, Tian S, Wang X, Douglas SD, Ho WZ (2002) Morphine enhances HIV infection of human blood mononuclear phagocytes through modulation of beta-chemokines and CCR5 receptor. J Investig Med 50:435–442. https://doi.org/10.1136/jim-50-06-03
Han C et al (2020) Morphine induces the differentiation of T helper cells to Th2 effector cells via the PKC-theta-GATA3 pathway. Int Immunopharmacol 80:106133. https://doi.org/10.1016/j.intimp.2019.106133
Harari Y, Weisbrodt NW, Moody FG (2006) The effect of morphine on mast cell-mediated mucosal permeability. Surgery 139:54–60. https://doi.org/10.1016/j.surg.2005.07.009
Hauser KF, Fitting S, Dever SM, Podhaizer EM, Knapp PE (2012) Opiate drug use and the pathophysiology of neuroAIDS. Curr HIV Res 10:435–452. https://doi.org/10.2174/157016212802138779
Hawkins BT, Davis TP (2005) The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev 57:173–185. https://doi.org/10.1124/pr.57.2.4
Hollenbach R et al (2014) Effect of morphine and SIV on dendritic cell trafficking into the central nervous system of rhesus macaques. J Neurovirol 20:175–183. https://doi.org/10.1007/s13365-013-0182-x
Hu G et al (2012) Exosome-mediated shuttling of microRNA-29 regulates HIV tat and morphine-mediated neuronal dysfunction. Cell Death Dis 3:e381. https://doi.org/10.1038/cddis.2012.114
Jordan A, Defechereux P, Verdin E (2001) The site of HIV-1 integration in the human genome determines basal transcriptional activity and response to tat transactivation. EMBO J 20:1726–1738. https://doi.org/10.1093/emboj/20.7.1726
Kapadia F, Vlahov D, Donahoe RM, Friedland G (2005) The role of substance abuse in HIV disease progression: reconciling differences from laboratory and epidemiologic investigations. Clin Infect Dis 41:1027–1034. https://doi.org/10.1086/433175
Karki S, Timilsina S, Sharma S (2018) Does morphine influence blood count in palliative patients? : A longitudinal study from an oncology Center in Nepal. J Pain Manag Med 04 https://doi.org/10.35248/2684-1320.18.4.134
Kauder SE, Bosque A, Lindqvist A, Planelles V, Verdin E (2009) Epigenetic regulation of HIV-1 latency by cytosine methylation. PLoS Pathog 5:e1000495. https://doi.org/10.1371/journal.ppat.1000495
Kelschenbach J, Barke RA, Roy S (2005) Morphine withdrawal contributes to Th cell differentiation by biasing cells toward the Th2 lineage. J Immunol 175:2655–2665. https://doi.org/10.4049/jimmunol.175.4.2655
Kelschenbach J, Ninkovic J, Wang J, Krishnan A, Charboneau R, Barke RA, Roy S (2008) Morphine withdrawal inhibits IL-12 induction in a macrophage cell line through a mechanism that involves cAMP. J Immunol 180:3670–3679. https://doi.org/10.4049/jimmunol.180.6.3670
Khabbazi S, Goumon Y, Parat MO (2015) Morphine modulates Interleukin-4- or breast Cancer cell-induced pro-metastatic activation of macrophages. Sci Rep 5:11389. https://doi.org/10.1038/srep11389
Kim S, Hahn YK, Podhaizer EM, McLane VD, Zou S, Hauser KF, Knapp PE (2018) A central role for glial CCR5 in directing the neuropathological interactions of HIV-1 tat and opiates. J Neuroinflammation 15:285. https://doi.org/10.1186/s12974-018-1320-4
Kovalevich J, Langford D (2012) Neuronal toxicity in HIV CNS disease. Future Virol 7:687–698. https://doi.org/10.2217/fvl.12.57
Krashin DL, Merrill JO, Trescot AM (2012) Opioids in the management of HIV-related pain. Pain Physician 15:ES157–ES168
Kumar R et al (2004) Modulation by morphine of viral set point in rhesus macaques infected with simian immunodeficiency virus and simian-human immunodeficiency virus. J Virol 78:11425–11428. https://doi.org/10.1128/JVI.78.20.11425-11428.2004
Kumar R et al (2006) Chronic morphine exposure causes pronounced virus replication in cerebral compartment and accelerated onset of AIDS in SIV/SHIV-infected Indian rhesus macaques. Virology 354:192–206. https://doi.org/10.1016/j.virol.2006.06.020
Lapierre J, Rodriguez M, Ojha CR, El-Hage N (2018) Critical role of Beclin1 in HIV tat and morphine-induced inflammation and calcium release in glial cells from autophagy deficient mouse. J Neuroimmune Pharmacol 13:355–370. https://doi.org/10.1007/s11481-018-9788-3
Lefkowitz SS, Chiang CY (1975) Effects of certain abused drug s on hemolysin forming cells. Life Sci 17:1763–1767. https://doi.org/10.1016/0024-3205(75)90458-0
Leo S, Nuydens R, Meert TF (2009) Opioid-induced proliferation of vascular endothelial cells. J Pain Res 2:59–66. https://doi.org/10.2147/jpr.s4748
Li Y et al (2003) Morphine enhances HIV infection of neonatal macrophages. Pediatr Res 54:282–288. https://doi.org/10.1203/01.PDR.0000074973.83826.4C
Li BH et al (2012) Stat6 activity-related Th2 cytokine profile and tumor growth advantage of human colorectal cancer cells in vitro and in vivo. Cell Signal 24:718–725. https://doi.org/10.1016/j.cellsig.2011.11.005
Liu B, Liu X, Tang SJ (2016) Interactions of Opioids and HIV Infection in the Pathogenesis of Chronic Pain. Front Microbiol 7:103. https://doi.org/10.3389/fmicb.2016.00103
Luk K, Boatman S, Johnson KN, Dudek OA, Ristau N, Vang D, Nguyen J, Gupta K (2012) Influence of morphine on pericyte-endothelial interaction: implications for antiangiogenic therapy. J Oncol 2012:458385–458310. https://doi.org/10.1155/2012/458385
Lum PJ, Tulsky JP (2006) The medical management of opioid dependence in HIV primary care settings. Curr HIV/AIDS Rep 3:195–204. https://doi.org/10.1007/s11904-006-0016-z
Ma J, Wang J, Wan J, Charboneau R, Chang Y, Barke RA, Roy S (2010) Morphine disrupts interleukin-23 (IL-23)/IL-17-mediated pulmonary mucosal host defense against Streptococcus pneumoniae infection. Infect Immun 78:830–837. https://doi.org/10.1128/IAI.00914-09
Madera-Salcedo IK, Cruz SL, Gonzalez-Espinosa C (2011) Morphine decreases early peritoneal innate immunity responses in Swiss-Webster and C57BL6/J mice through the inhibition of mast cell TNF-alpha release. J Neuroimmunol 232:101–107. https://doi.org/10.1016/j.jneuroim.2010.10.017
Madera-Salcedo IK, Cruz SL, Gonzalez-Espinosa C (2013) Morphine prevents lipopolysaccharide-induced TNF secretion in mast cells blocking IkappaB kinase activation and SNAP-23 phosphorylation: correlation with the formation of a beta-arrestin/TRAF6 complex. J Immunol 191:3400–3409. https://doi.org/10.4049/jimmunol.1202658
Mahajan SD, Aalinkeel R, Reynolds JL, Nair BB, Fernandez SF, Schwartz SA, Nair MP (2005a) Morphine exacerbates HIV-1 viral protein gp120 induced modulation of chemokine gene expression in U373 astrocytoma cells. Curr HIV Res 3:277–288. https://doi.org/10.2174/1570162054368048
Mahajan SD, Schwartz SA, Aalinkeel R, Chawda RP, Sykes DE, Nair MP (2005b) Morphine modulates chemokine gene regulation in normal human astrocytes. Clin Immunol 115:323–332. https://doi.org/10.1016/j.clim.2005.02.004
Mahajan SD, Aalinkeel R, Sykes DE, Reynolds JL, Bindukumar B, Fernandez SF, Chawda R, Shanahan TC, Schwartz SA (2008) Tight junction regulation by morphine and HIV-1 tat modulates blood-brain barrier permeability. J Clin Immunol 28:528–541. https://doi.org/10.1007/s10875-008-9208-1
Mahajan SD et al (2017) Immunomodulatory role of complement proteins in the neuropathology associated with opiate abuse and HIV-1 co-morbidity. Immunol Invest 46:816–832. https://doi.org/10.1080/08820139.2017.1371891
Malik S, Khalique H, Buch S, Seth P (2011) A growth factor attenuates HIV-1 tat and morphine induced damage to human neurons: implication in HIV/AIDS-drug abuse cases. PLoS One 6:e18116. https://doi.org/10.1371/journal.pone.0018116
Marcario JK et al (2008) Effect of morphine on the neuropathogenesis of SIVmac infection in Indian rhesus macaques. J Neuroimmune Pharmacol 3:12–25. https://doi.org/10.1007/s11481-007-9085-z
Maricato JT et al (2015) Epigenetic modulations in activated cells early after HIV-1 infection and their possible functional consequences. PLoS One 10:e0119234. https://doi.org/10.1371/journal.pone.0119234
Martin JL, Koodie L, Krishnan AG, Charboneau R, Barke RA, Roy S (2010) Chronic morphine administration delays wound healing by inhibiting immune cell recruitment to the wound site. Am J Pathol 176:786–799. https://doi.org/10.2353/ajpath.2010.090457
Masvekar RR, El-Hage N, Hauser KF, Knapp PE (2014) Morphine enhances HIV-1SF162-mediated neuron death and delays recovery of injured neurites. PLoS One 9:e100196. https://doi.org/10.1371/journal.pone.0100196
Masvekar RR, El-Hage N, Hauser KF, Knapp PE (2015) GSK3beta-activation is a point of convergence for HIV-1 and opiate-mediated interactive neurotoxicity. Mol Cell Neurosci 65:11–20. https://doi.org/10.1016/j.mcn.2015.01.001
Mellon RD, Bayer BM (2001) Reversal of acute effects of high dose morphine on lymphocyte activity by chlorisondamine. Drug Alcohol Depend 62:141–147. https://doi.org/10.1016/s0376-8716(00)00184-8
Meng J, Banerjee S, Li D, Sindberg GM, Wang F, Ma J, Roy S (2015a) Opioid exacerbation of gram-positive sepsis, induced by gut microbial modulation, is rescued by IL-17A neutralization. Sci Rep 5:10918. https://doi.org/10.1038/srep10918
Meng J, Sindberg GM, Roy S (2015b) Disruption of gut homeostasis by opioids accelerates HIV disease progression. Front Microbiol 6:643. https://doi.org/10.3389/fmicb.2015.00643
Mercer SL, Coop A (2011) Opioid analgesics and P-glycoprotein efflux transporters: a potential systems-level contribution to analgesic tolerance. Curr Top Med Chem 11:1157–1164. https://doi.org/10.2174/156802611795371288
Merlin JS, Bulls HW, Vucovich LA, Edelman EJ, Starrels JL (2016) Pharmacologic and non-pharmacologic treatments for chronic pain in individuals with HIV: a systematic review. AIDS Care 28:1506–1515. https://doi.org/10.1080/09540121.2016.1191612
Miyagi T, Chuang LF, Doi RH, Carlos MP, Torres JV, Chuang RY (2000) Morphine induces gene expression of CCR5 in human CEMx174 lymphocytes. J Biol Chem 275:31305-31310. https://doi.org/10.1074/jbc.M001269200
Mutua JM, Perelson AS, Kumar A, Vaidya NK (2019) Modeling the Effects of Morphine-Altered Virus Specific Antibody Responses on HIV/SIV Dynamics. Sci Rep 9:5423. https://doi.org/10.1038/s41598-019-41751-8
Nath A (2002) Human immunodeficiency virus (HIV) proteins in neuropathogenesis of HIV dementia. J Infect Dis 186(Suppl 2):S193–S198. https://doi.org/10.1086/344528
Nath A et al (2000) Neurotoxicity and dysfunction of dopaminergic systems associated with AIDS dementia. J Psychopharmacol 14:222–227. https://doi.org/10.1177/026988110001400305
Nath A, Hauser KF, Wojna V, Booze RM, Maragos W, Prendergast M, Cass W, Turchan JT (2002) Molecular basis for interactions of HIV and drugs of abuse. J Acquir Immune Defic Syndr 31(Suppl 2):S62–S69. https://doi.org/10.1097/00126334-200210012-00006
Nguyen J et al (2014) Morphine stimulates cancer progression and mast cell activation and impairs survival in transgenic mice with breast cancer. Br J Anaesth 113(Suppl 1):i4–i13. https://doi.org/10.1093/bja/aeu090
Noel RJ Jr, Rivera-Amill V, Buch S, Kumar A (2008) Opiates, immune system, acquired immunodeficiency syndrome, and nonhuman primate model. J Neurovirol 14:279–285. https://doi.org/10.1080/13550280802078209
Norman LR, Kumar A (2006) Neuropscyhological Complications of HIV Disease and Substances of Abuse. Am J Infect Dis 2:67–73. https://doi.org/10.3844/ajidsp.2006.67.73
Pirastu R, Fais R, Messina M, Bini V, Spiga S, Falconieri D, Diana M (2006) Impaired decision-making in opiate-dependent subjects: effect of pharmacological therapies. Drug Alcohol Depend 83:163–168. https://doi.org/10.1016/j.drugalcdep.2005.11.008
Plytycz B, Natorska J (2002) Morphine attenuates pain and prevents inflammation in experimental peritonitis. Trends Immunol 23:345–346. https://doi.org/10.1016/s1471-4906(02)02257-3
Prottengeier J, Koutsilieri E, Scheller C (2014) The effects of opioids on HIV reactivation in latently-infected T-lymphoblasts. AIDS Res Ther 11:17. https://doi.org/10.1186/1742-6405-11-17
Rahim RT, Adler MW, Meissler JJ Jr, Cowan A, Rogers TJ, Geller EB, Eisenstein TK (2002) Abrupt or precipitated withdrawal from morphine induces immunosuppression. J Neuroimmunol 127:88–95. https://doi.org/10.1016/s0165-5728(02)00103-0
Rahim RT, Meissler JJ Jr, Adler MW, Eisenstein TK (2005) Splenic macrophages and B cells mediate immunosuppression following abrupt withdrawal from morphine. J Leukoc Biol 78:1185–1191. https://doi.org/10.1189/jlb.0304123
Reynolds JL et al (2012) Morphine and galectin-1 modulate HIV-1 infection of human monocyte-derived macrophages. J Immunol 188:3757–3765. https://doi.org/10.4049/jimmunol.1102276
Rivera-Amill V, Silverstein PS, Noel RJ Jr, Kumar S, Kumar A (2010) Morphine and rapid disease progression in nonhuman primate model of AIDS: inverse correlation between disease progression and virus evolution. J NeuroImmune Pharmacol 5:122–132. https://doi.org/10.1007/s11481-009-9184-0
Rodriguez M et al. (2017) Importance of autophagy in mediating human immunodeficiency virus (HIV) and morphine-induced metabolic dysfunction and inflammation in human astrocytes. Viruses 9 https://doi.org/10.3390/v9080201
Rojavin M, Szabo I, Bussiere JL, Rogers TJ, Adler MW, Eisenstein TK (1993) Morphine treatment in vitro or in vivo decreases phagocytic functions of murine macrophages. Life Sci 53:997–1006. https://doi.org/10.1016/0024-3205(93)90122-j
Roy S, Chapin RB, Cain KJ, Charboneau RG, Ramakrishnan S, Barke RA (1997) Morphine inhibits transcriptional activation of IL-2 in mouse thymocytes. Cell Immunol 179:1–9. https://doi.org/10.1006/cimm.1997.1147
Roy S et al (2001) Morphine directs T cells toward T(H2) differentiation. Surgery 130:304–309. https://doi.org/10.1067/msy.2001.116033
Roy S, Wang J, Gupta S, Charboneau R, Loh HH, Barke RA (2004) Chronic morphine treatment differentiates T helper cells to Th2 effector cells by modulating transcription factors GATA 3 and T-bet. J Neuroimmunol 147:78–81. https://doi.org/10.1016/j.jneuroim.2003.10.016
Roy S, Wang J, Charboneau R, Loh HH, Barke RA (2005) Morphine induces CD4+ T cell IL-4 expression through an adenylyl cyclase mechanism independent of the protein kinase a pathway. J Immunol 175:6361–6367. https://doi.org/10.4049/jimmunol.175.10.6361
Roy S, Wang J, Kelschenbach J, Koodie L, Martin J (2006) Modulation of immune function by morphine: implications for susceptibility to infection. J NeuroImmune Pharmacol 1:77–89. https://doi.org/10.1007/s11481-005-9009-8
Roy S, Ninkovic J, Banerjee S, Charboneau RG, Das S, Dutta R, Kirchner VA, Koodie L, Ma J, Meng J, Barke RA (2011) Opioid drug abuse and modulation of immune function: consequences in the susceptibility to opportunistic infections. J NeuroImmune Pharmacol 6:442–465. https://doi.org/10.1007/s11481-011-9292-5
Ru W, Tang SJ (2017) HIV-associated synaptic degeneration. Mol Brain 10:40. https://doi.org/10.1186/s13041-017-0321-z
Sacerdote P (2006) Opioids and the immune system. Palliat Med 20(Suppl 1):s9–s15
Samikkannu T, Ranjith D, Rao KV, Atluri VS, Pimentel E, El-Hage N, Nair MP (2015) HIV-1 gp120 and morphine induced oxidative stress: role in cell cycle regulation. Front Microbiol 6:614. https://doi.org/10.3389/fmicb.2015.00614
Saurer TB, Carrigan KA, Ijames SG, Lysle DT (2006a) Suppression of natural killer cell activity by morphine is mediated by the nucleus accumbens shell. J Neuroimmunol 173:3–11. https://doi.org/10.1016/j.jneuroim.2005.11.009
Saurer TB, Ijames SG, Lysle DT (2006b) Neuropeptide Y Y1 receptors mediate morphine-induced reductions of natural killer cell activity. J Neuroimmunol 177:18–26. https://doi.org/10.1016/j.jneuroim.2006.05.002
Sharma HS, Ali SF (2006) Alterations in blood-brain barrier function by morphine and methamphetamine. Ann N Y Acad Sci 1074:198–224. https://doi.org/10.1196/annals.1369.020
Sharma HS, Sjoquist PO, Ali SF (2010) Alterations in blood-brain barrier function and brain pathology by morphine in the rat. Neuroprotective effects of antioxidant H-290/51. Acta Neurochir Suppl 106:61–66. https://doi.org/10.1007/978-3-211-98811-4_10
Sharp BM, Keane WF, Suh HJ, Gekker G, Tsukayama D, Peterson PK (1985) Opioid peptides rapidly stimulate superoxide production by human polymorphonuclear leukocytes and macrophages. Endocrinology 117:793–795. https://doi.org/10.1210/endo-117-2-793
Shavit Y et al (1986) Involvement of brain opiate receptors in the immune-suppressive effect of morphine. Proc Natl Acad Sci U S A 83:7114–7117. https://doi.org/10.1073/pnas.83.18.7114
Shavit Y et al (1987) Effects of a single administration of morphine or footshock stress on natural killer cell cytotoxicity. Brain Behav Immun 1:318–328. https://doi.org/10.1016/0889-1591(87)90034-1
Shawahna R et al (2011) Transcriptomic and quantitative proteomic analysis of transporters and drug metabolizing enzymes in freshly isolated human brain microvessels. Mol Pharm 8:1332–1341. https://doi.org/10.1021/mp200129p
Shirazi J, Shah S, Sagar D, Nonnemacher MR, Wigdahl B, Khan ZK, Jain P (2013) Epigenetics, drugs of abuse, and the retroviral promoter. J NeuroImmune Pharmacol 8:1181–1196. https://doi.org/10.1007/s11481-013-9508-y
Sil S, Periyasamy P, Guo ML, Callen S, Buch S (2018) Morphine-Mediated Brain Region-Specific Astrocytosis Involves the ER Stress-Autophagy Axis. Mol Neurobiol 55:6713–6733. https://doi.org/10.1007/s12035-018-0878-2
Simpkins CO, Alailima ST, Tate EA, Johnson M (1986) The effect of enkephalins and prostaglandins on O-2 release by neutrophils. J Surg Res 41:645–652. https://doi.org/10.1016/0022-4804(86)90090-9
Singhal PC, Sharma P, Kapasi AA, Reddy K, Franki N, Gibbons N (1998) Morphine enhances macrophage apoptosis. J Immunol 160:1886–1893
Spijkerman IJ et al (1996) Differences in progression to AIDS between injection drug users and homosexual men with documented dates of seroconversion. Epidemiology 7:571–577. https://doi.org/10.1097/00001648-199611000-00002
Stankiewicz E, Wypasek E, Plytycz B (2004) Mast cells are responsible for the lack of anti-inflammatory effects of morphine in CBA mice. Mediators Inflamm 13:365–368. https://doi.org/10.1080/09629350400008778
Steele AD, Henderson EE, Rogers TJ (2003) Mu-opioid modulation of HIV-1 coreceptor expression and HIV-1 replication. Virology 309:99–107. https://doi.org/10.1016/s0042-6822(03)00015-1
Suzuki S, Chuang AJ, Chuang LF, Doi RH, Chuang RY (2002) Morphine promotes simian acquired immunodeficiency syndrome virus replication in monkey peripheral mononuclear cells: induction of CC chemokine receptor 5 expression for virus entry. J Infect Dis 185:1826–1829. https://doi.org/10.1086/340816
Szabo I, Rojavin M, Bussiere JL, Eisenstein TK, Adler MW, Rogers TJ (1993) Suppression of peritoneal macrophage phagocytosis of Candida albicans by opioids. J Pharmacol Exp Ther 267:703–706
Tabellini G et al (2014) Effects of opioid therapy on human natural killer cells. Int Immunopharmacol 18:169–174. https://doi.org/10.1016/j.intimp.2013.11.015
Tahamtan A, Tavakoli-Yaraki M, Mokhtari-Azad T, Teymoori-Rad M, Bont L, Shokri F, Salimi V (2016) Opioids and Viral Infections: A Double-Edged Sword. Sword Front Microbiol 7:970. https://doi.org/10.3389/fmicb.2016.00970
Thorpe LE, Frederick M, Pitt J, Cheng I, Watts DH, Buschur S, Green K, Zorrilla C, Landesman SH, Hershow RC (2004) Effect of hard-drug use on CD4 cell percentage. J Acquir Immune Defic Syndr 37:1423–1430. https://doi.org/10.1097/01.qai.0000127354.78706.5d
Tirado G, Kumar A (2006) Evolution of SIV envelope in morphine-dependent rhesus macaques with rapid disease progression AIDS. Res Hum Retroviruses 22:114–119. https://doi.org/10.1089/aid.2006.22.114
Tomei EZ, Renaud FL (1997) Effect of morphine on Fc-mediated phagocytosis by murine macrophages in vitro. J Neuroimmunol 74:111–116. https://doi.org/10.1016/s0165-5728(96)00213-5
Tunblad K, Jonsson EN, Hammarlund-Udenaes M (2003) Morphine blood-brain barrier transport is influenced by probenecid co-administration. Pharm Res 20:618–623. https://doi.org/10.1023/a:1023250900462
Turchan-Cholewo J, Dimayuga FO, Ding Q, Keller JN, Hauser KF, Knapp PE, Bruce-Keller AJ (2008) Cell-specific actions of HIV-tat and morphine on opioid receptor expression in glia. J Neurosci Res 86:2100–2110. https://doi.org/10.1002/jnr.21653
Turchan-Cholewo J, Dimayuga FO, Gupta S, Keller JN, Knapp PE, Hauser KF, Bruce-Keller AJ (2009) Morphine and HIV-Tat increase microglial-free radical production and oxidative stress: possible role in cytokine regulation. J Neurochem 108:202–215. https://doi.org/10.1111/j.1471-4159.2008.05756.x
Tyagi M, Pearson RJ, Karn J (2010) Establishment of HIV latency in primary CD4+ cells is due to epigenetic transcriptional silencing and P-TEFb restriction. J Virol 84:6425–6437. https://doi.org/10.1128/JVI.01519-09
Tyagi M, Bukrinsky M, Simon GL (2016) Mechanisms of HIV Transcriptional Regulation by Drugs of Abuse. Curr HIV Res 14:442–454. https://doi.org/10.2174/1570162x14666160324124736
Uchida Y, Ohtsuki S, Katsukura Y, Ikeda C, Suzuki T, Kamiie J, Terasaki T (2011) Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors. J Neurochem 117:333–345. https://doi.org/10.1111/j.1471-4159.2011.07208.x
Vaidya NK, Ribeiro RM, Perelson AS, Kumar A (2016) PLoS Comput Biol 12:e1005127 https://doi.org/10.1371/journal.pcbi.1005127, Modeling the Effects of Morphine on Simian Immunodeficiency Virus Dynamics
Vandegraaff N, Devroe E, Turlure F, Silver PA, Engelman A (2006) Biochemical and genetic analyses of integrase-interacting proteins lens epithelium-derived growth factor (LEDGF)/p75 and hepatoma-derived growth factor related protein 2 (HRP2) in preintegration complex function and HIV-1 replication. Virology 346:415–426. https://doi.org/10.1016/j.virol.2005.11.022
Verdin E (1991) DNase I-hypersensitive sites are associated with both long terminal repeats and with the intragenic enhancer of integrated human immunodeficiency virus type 1. J Virol 65:6790–6799
Verdin E, Paras P Jr, Van Lint C (1993) Chromatin disruption in the promoter of human immunodeficiency virus type 1 during transcriptional activation. EMBO J 12:3249–3259
Wang J, Charboneau R, Balasubramanian S, Barke RA, Loh HH, Roy S (2002) The immunosuppressive effects of chronic morphine treatment are partially dependent on corticosterone and mediated by the mu-opioid receptor. J Leukoc Biol 71:782–790
Wang X, Tan N, Douglas SD, Zhang T, Wang YJ, Ho WZ (2005) Morphine inhibits CD8+ T cell-mediated, noncytolytic, anti-HIV activity in latently infected immune cells. J Leukoc Biol 78:772–776. https://doi.org/10.1189/jlb.0305167
Wang GP, Ciuffi A, Leipzig J, Berry CC, Bushman FD (2007a) HIV integration site selection: analysis by massively parallel pyrosequencing reveals association with epigenetic modifications. Genome Res 17:1186–1194. https://doi.org/10.1101/gr.6286907
Wang J, Barke RA, Roy S (2007b) Transcriptional and epigenetic regulation of interleukin-2 gene in activated T cells by morphine. J Biol Chem 282:7164–7171. https://doi.org/10.1074/jbc.M604367200
Wang J, Barke RA, Charboneau R, Schwendener R, Roy S (2008) Morphine induces defects in early response of alveolar macrophages to Streptococcus pneumoniae by modulating TLR9-NF-kappa B signaling. J Immunol 180:3594–3600. https://doi.org/10.4049/jimmunol.180.5.3594
Wang X, Ye L, Hou W, Zhou Y, Wang YJ, Metzger DS, Ho WZ (2009) Cellular microRNA expression correlates with susceptibility of monocytes/macrophages to HIV-1 infection. Blood 113:671–674. https://doi.org/10.1182/blood-2008-09-175000
Wang J, Ma J, Charboneau R, Barke R, Roy S (2011a) Morphine inhibits murine dendritic cell IL-23 production by modulating toll-like receptor 2 and Nod2 signaling. J biol Chem 286:10225–10232. https://doi.org/10.1074/jbc.M110.188680
Wang X, Ye L, Zhou Y, Liu MQ, Zhou DJ, Ho WZ (2011b) Inhibition of anti-HIV microRNA expression: a mechanism for opioid-mediated enhancement of HIV infection of monocytes. Am J Pathol 178:41–47. https://doi.org/10.1016/j.ajpath.2010.11.042
Wang Y, Wang X, Ye L, Li J, Song L, Fulambarkar N, Ho W (2012) Morphine suppresses IFN signaling pathway and enhances AIDS virus infection. PLoS One 7:e31167. https://doi.org/10.1371/journal.pone.0031167
Weber RJ, Pert A (1989) The periaqueductal gray matter mediates opiate-induced immunosuppression. Science 245:188–190. https://doi.org/10.1126/science.2749256
Weber RJ, Ikejiri B, Rice KC, Pert A, Hagan AA (1987) Opiate receptor mediated regulation of the immune response in vivo NIDA. Res Monogr 76:341–348
Welters ID (2003) Is immunomodulation by opioid drugs of clinical relevance? Curr Opin Anaesthesiol 16:509–513. https://doi.org/10.1097/00001503-200310000-00011
West JP, Dykstra LA, Lysle DT (1999) Immunomodulatory effects of morphine withdrawal in the rat are time dependent and reversible by clonidine. Psychopharmacology (Berl) 146:320–327. https://doi.org/10.1007/s002130051123
Yeager MP, Colacchio TA, Yu CT, Hildebrandt L, Howell AL, Weiss J, Guyre PM (1995) Morphine inhibits spontaneous and cytokine-enhanced natural killer cell cytotoxicity in volunteers. Anesthesiology 83:500–508. https://doi.org/10.1097/00000542-199509000-00008
Yin D, Mufson RA, Wang R, Shi Y (1999) Fas-mediated cell death promoted by opioids. Nature 397:218. https://doi.org/10.1038/16612
Yossuck P, Nightengale BJ, Fortney JE, Gibson LF (2008)Effect of morphine sulfate on neonatal neutrophil chemotaxis Clin J Pain 24:76–82 https://doi.org/10.1097/AJP.0b013e3181582c76
Youn GS, Cho H, Kim D, Choi SY, Park J (2017) Crosstalk between HDAC6 and Nox2-based NADPH oxidase mediates HIV-1 tat-induced pro-inflammatory responses in astrocytes. Redox Biol 12:978–986. https://doi.org/10.1016/j.redox.2017.05.001
Zou S, Fitting S, Hahn YK, Welch SP, El-Hage N, Hauser KF, Knapp PE (2011) Morphine potentiates neurodegenerative effects of HIV-1 tat through actions at mu-opioid receptor-expressing glia. Brain 134:3616–3631. https://doi.org/10.1093/brain/awr281
Funding
This work is supported by NIH grants - DA040397, DA041751, MH062261, DA043164, DA044586, and Nebraska Center for Substance Abuse Research.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Buch, S., Periyasamy, P., Thangaraj, A. et al. Opioid-Mediated HIV-1 Immunopathogenesis. J Neuroimmune Pharmacol 15, 628–642 (2020). https://doi.org/10.1007/s11481-020-09960-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11481-020-09960-5