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Morphine Potentiates Neuropathogenesis of SIV Infection in Rhesus Macaques

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Abstract

Despite the advent of antiretroviral therapy, complications of HIV-1 infection with concurrent drug abuse are an emerging problem. Opiates are well known to modulate immune responses by preventing the development of cell-mediated immune responses. Their effect on the pathogenesis of HIV-1 infection however remains controversial. Using the simian immunodeficiency virus/macaque model of HIV pathogenesis, we sought to explore the impact of morphine on disease progression and pathogenesis. Sixteen rhesus macaques were divided into two groups; four were administered saline and 12 others morphine routinely. Both groups of animals were then inoculated with SIVmacR71/17E and followed longitudinally for disease pathogenesis. The morphine group (M+V) exhibited a trend towards higher mortality rates and retardation in weight gain compared to the virus-alone group. Interestingly, a subset of M+V animals succumbed to disease within weeks post-infection. These rapid progressors also exhibited a higher incidence of other end-organ pathologies. Despite the higher numbers of circulating CD4+ and CD8+ T cells in the M+V group, CD4/CD8 ratios between the groups remained unchanged. Plasma and CSF viral load in the M+V group was at least a log higher than the control group. Similarly, there was a trend toward increased virus build-up in the brains of M+V animals compared with controls. A novel finding of this study was the increased influx of infected monocyte/macrophages in the brains of M+V animals.

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References

  • Anghel A, Jamieson CA, Ren X, Young J, Porche R, Ozigbo E, Ghods DE, Lee ML, Liu Y, Lutfy K, Friedman TC (2010) Gene expression profiling following short-term and long-term morphine exposure in mice uncovers genes involved in food intake. Neuroscience 167:554–566

    Article  PubMed  CAS  Google Scholar 

  • Bell JE, Donaldson YK, Lowrie S, McKenzie CA, Elton RA, Chiswick A, Brettle RP, Ironside JW, Simmonds P (1996) Influence of risk group and zidovudine therapy on the development of HIV encephalitis and cognitive impairment in AIDS patients. AIDS 10:493–499

    Article  PubMed  CAS  Google Scholar 

  • Bokhari SM, Yao H, Bethel-Brown C, Fuwang P, Williams R, Dhillon NK, Hegde R, Kumar A, Buch SJ (2009) Morphine enhances Tat-induced activation in murine microglia. J Neurovirol 15:219–228

    Article  PubMed  CAS  Google Scholar 

  • Bouwman FH, Skolasky RL, Hes D, Selnes OA, Glass JD, Nance-Sproson TE, Royal W, Dal Pan GJ, McArthur JC (1998) Variable progression of HIV-associated dementia. Neurology 50:1814–1820

    PubMed  CAS  Google Scholar 

  • Chen Z, Zhou P, Ho DD, Landau NR, Marx PA (1997) Genetically divergent strains of simian immunodeficiency virus use CCR5 as a coreceptor for entry. J Virol 71:2705–2714

    PubMed  CAS  Google Scholar 

  • Chiesi A, Vella S, Dally LG, Pedersen C, Danner S, Johnson AM, Schwander S, Goebel FD, Glauser M, Antunes F et al (1996) Epidemiology of AIDS dementia complex in Europe. AIDS in Europe Study Group. J Acquir Immune Defic Syndr Human Retrovirol 11:39–44

    Article  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Chuang RY, Suzuki S, Chuang TK, Miyagi T, Chuang LF, Doi RH (2005) Opioids and the progression of simian AIDS. Front Biosci 10:1666–1677

    Article  PubMed  CAS  Google Scholar 

  • Donahoe RM (2004) Multiple ways that drug abuse might influence AIDS progression: clues from a monkey model. J Neuroimmunol 147:28–32

    Article  PubMed  CAS  Google Scholar 

  • Donahoe RM, Vlahov D (1998) Opiates as potential cofactors in progression of HIV-1 infections to AIDS. J Neuroimmunol 83:77–87

    Article  PubMed  CAS  Google Scholar 

  • Donahoe RM, O’Neil SP, Marsteller FA, Novembre FJ, Anderson DC, Lankford-Turner P, McClure HH (2009) Probable deceleration of progression of simian AIDS affected by opiate dependency: studies with a rhesus macaque/SIVsmm9 model. J Acquir Immune Defic Syndr 50:241–249

    Article  PubMed  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Getts DR, Terry RL, Getts MT, Muller M, Rana S, Shrestha B, Radford J, Van Rooijen N, Campbell IL, King NJ (2008) Ly6c+ “inflammatory monocytes” are microglial precursors recruited in a pathogenic manner in West Nile virus encephalitis. J Exp Med 205:2319–2337

    Article  PubMed  CAS  Google Scholar 

  • Goodkin K, Shapshak P, Metsch LR, McCoy CB, Crandall KA, Kumar M, Fujimura RK, McCoy V, Zhang BT, Reyblat S, Xin KQ, Kumar AM (1998) Cocaine abuse and HIV-1 infection: epidemiology and neuropathogenesis. J Neuroimmunol 83:88–101

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Kirchhoff F, Pohlmann S, Hamacher M, Means RE, Kraus T, Uberla K, Di Marzio P (1997) Simian immunodeficiency virus variants with differential T-cell and macrophage tropism use CCR5 and an unidentified cofactor expressed in CEMx174 cells for efficient entry. J Virol 71:6509–6516

    PubMed  CAS  Google Scholar 

  • Koenig S, Gendelman HE, Orenstein JM, Dal Canto MC, Pezeshkpour GH, Yungbluth M, Janotta F, Aksamit A, Martin MA, Fauci AS (1986) Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science 233:1089–1093

    Article  PubMed  CAS  Google Scholar 

  • Kumar R, Torres C, Yamamura Y, Rodriguez I, Martinez M, Staprans S, Donahoe RM, Kraiselburd E, Stephens EB, Kumar A (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

    Article  PubMed  CAS  Google Scholar 

  • Kumar R, Orsoni S, Norman L, Verma AS, Tirado G, Giavedoni LD, Staprans S, Miller GM, Buch SJ, Kumar A (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

    Article  PubMed  CAS  Google Scholar 

  • Li Q, Gebhard K, Schacker T, Henry K, Haase AT (1997) The relationship between tumor necrosis factor and human immunodeficiency virus gene expression in lymphoid tissue. J Virol 71:7080–7082

    PubMed  CAS  Google Scholar 

  • Mackay GA, Liu Z, Singh DK, Smith MS, Mukherjee S, Sheffer D, Jia F, Adany I, Sun KH, Dhillon S, Zhuge W, Narayan O (2004) Protection against late-onset AIDS in macaques prophylactically immunized with a live simian HIV vaccine was dependent on persistence of the vaccine virus. J Immunol 173:4100–4107

    PubMed  CAS  Google Scholar 

  • Marcario JK, Riazi M, Adany I, Kenjale H, Fleming K, Marquis J, Nemon O, Mayo MS, Yankee T, Narayan O, Cheney PD (2008) Effect of morphine on the neuropathogenesis of SIVmac infection in Indian rhesus macaques. J Neuroimmune Pharmacol 3:12–25

    Article  PubMed  Google Scholar 

  • Martinez AJ, Sell M, Mitrovics T, Stoltenburg-Didinger G, Iglesias-Rozas JR, Giraldo-Velasquez MA, Gosztonyi G, Schneider V, Cervos-Navarro J (1995) The neuropathology and epidemiology of AIDS. A Berlin experience. A review of 200 cases. Pathol Res Pract 191:427–443

    Article  PubMed  CAS  Google Scholar 

  • Marx PA, Chen Z (1998) The function of simian chemokine receptors in the replication of SIV. Semin Immunol 10:215–223

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Nath A, Maragos WF, Avison MJ, Schmitt FA, Berger JR (2001) Acceleration of HIV dementia with methamphetamine and cocaine. J Neurovirol 7:66–71

    Article  PubMed  CAS  Google Scholar 

  • Raghavan R, Cheney PD, Raymond LA, Joag SV, Stephens EB, Adany I, Pinson DM, Li Z, Marcario JK, Jia F, Wang C, Foresman L, Berman NE, Narayan O (1999) Morphological correlates of neurological dysfunction in macaques infected with neurovirulent simian immunodeficiency virus. Neuropathol Appl Neurobiol 25:285–294

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Spijkerman IJ, Langendam MW, Veugelers PJ, van Ameijden EJ, Keet IP, Geskus RB, van den Hoek A, Coutinho RA (1996) Differences in progression to AIDS between injection drug users and homosexual men with documented dates of seroconversion. Epidemiology 7:571–577

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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, HIV RNA level, and progression to AIDS-defining class C events among HIV-infected women. J Acquir Immune Defic Syndr 37:1423–1430

    Article  PubMed  CAS  Google Scholar 

  • Tomei EZ, Renaud FL (1997) Effect of morphine on Fc-mediated phagocytosis by murine macrophages in vitro. J Neuroimmunol 74:111–116

    Article  PubMed  CAS  Google Scholar 

  • Veazey RS, DeMaria M, Chalifoux LV, Shvetz DE, Pauley DR, Knight HL, Rosenzweig M, Johnson RP, Desrosiers RC, Lackner AA (1998) Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 280:427–431

    Article  PubMed  CAS  Google Scholar 

  • Veazey RS, Mansfield KG, Tham IC, Carville AC, Shvetz DE, Forand AE, Lackner AA (2000a) Dynamics of CCR5 expression by CD4(+) T cells in lymphoid tissues during simian immunodeficiency virus infection. J Virol 74:11001–11007

    Article  PubMed  CAS  Google Scholar 

  • Veazey RS, Tham IC, Mansfield KG, DeMaria M, Forand AE, Shvetz DE, Chalifoux LV, Sehgal PK, Lackner AA (2000b) Identifying the target cell in primary simian immunodeficiency virus (SIV) infection: highly activated memory CD4(+) T cells are rapidly eliminated in early SIV infection in vivo. J Virol 74:57–64

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by grant DA024442 from the National Institutes of Health (SB).

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Authors and Affiliations

  1. Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, 66160, USA

    Ramakrishna Hegde, Istvan Adany, Zhuang Li, Paul D. Cheney & Shilpa Buch

  2. Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, 66160, USA

    Hung-Wen Yeh

  3. Department of Pathology, University of Kansas Medical Center, Kansas City, KS, 66160, USA

    David Pinson

  4. Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St Louis, MO, 63110, USA

    Sirosh M. Bokhari

  5. Nebraska Center for Virology and School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, NE, 68583, USA

    Qingsheng Li

  6. Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center (DRC 8011), University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA

    Shannon Callen, Honghong Yao & Shilpa Buch

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  1. Sirosh M. Bokhari
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  2. Ramakrishna Hegde
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  3. Shannon Callen
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  4. Honghong Yao
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  5. Istvan Adany
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  6. Qingsheng Li
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  7. Zhuang Li
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  8. David Pinson
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  9. Hung-Wen Yeh
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  10. Paul D. Cheney
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  11. Shilpa Buch
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Corresponding author

Correspondence to Shilpa Buch.

Additional information

This manuscript is dedicated to the memory of a departed friend and colleague, Dr. Opendra “Bill” Narayan, for his passion and love for science.

Sirosh M. Bokhari and Ramakrishna Hegde contributed equally to this work.

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Bokhari, S.M., Hegde, R., Callen, S. et al. Morphine Potentiates Neuropathogenesis of SIV Infection in Rhesus Macaques. J Neuroimmune Pharmacol 6, 626–639 (2011). https://doi.org/10.1007/s11481-011-9272-9

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  • DOI: https://doi.org/10.1007/s11481-011-9272-9

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