Abstract
Since human immunodeficiency virus (HIV) and hepatitis C virus (HCV) share the same modes of transmission and common risk factors for infection, co-infections with HIV and HCV are frequently found in injection drug users (IDUs). IDUs represent one of the largest reservoirs of HIV as well as HCV in the United States. These two pathogens are also likely to be responsible for the highest infectious disease morbidity and mortality rates among IDUs. IDUs frequently involve the abuse of heroin, the most common abused opiate. Opiates have been suggested to have a cofactor role in the immunopathogenesis of HIV disease, as they have the potential to compromise host immune responses and enhances microbial infections. Although in vitro studies have yielded relatively agreeable data that morphine, the active metabolite of heroin, exacerbate HIV infection/replication, epidemiologic studies as well as in vivo non-human primate investigations on the impact of opiate abuse on HIV disease progression have yielded the conflicting data. Given immunomodulation and immunocompromising effect as well as demonstrated impact to enhance HIV replication in vitro, it is reasonable to believe that opiate abuse is a facilitator in HIV and/or HCV disease progression. However, much remain to be learned about the mechanisms of opiate-mediated broad influence on host immunity and viral expression. Thus, more extensive studies are needed in order to determine the effects of different conditions of opiate abuse and to define the understanding of the role of opiate in modulating HIV and/or HCV disease progression.
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Aitken CK, Lewis J, Tracy SL, Spelman T, Bowden DS, Bharadwaj M, Drummer H, Hellard M (2008) High incidence of hepatitis C virus reinfection in a cohort of injecting drug users. Hepatology 48:1746–1752
Alcabes P, Friedland G (1995) Injection drug use and human immunodeficiency virus infection. Clin Infect Dis 20:1467–1479
Alonzo NC, Bayer BM (2002) Opioids, immunology, and host defenses of intravenous drug abusers. Infect Dis Clin North Am 16:553–569
Alter MJ, Kruszon-Moran D, Nainan OV, McQuillan GM, Gao F, Moyer LA, Kaslow RA, Margolis HS (1999) The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 341:556–562
Ancuta P, Kamat A, Kunstman KJ, Kim EY, Autissier P, Wurcel A, Zaman T, Stone D, Mefford M, Morgello S, Singer EJ, Wolinsky SM, Gabuzda D (2008) Microbial translocation is associated with increased monocyte activation and dementia in AIDS patients. PLoS One 3:e2516
Asakura H, Kawamoto K, Igimi S, Yamamoto S, Makino S (2006) Enhancement of mice susceptibility to infection with Listeria monocytogenes by the treatment of morphine. Microbiol Immunol 50:543–547
Backmund M, Meyer K, Wachtler M, Eichenlaub D (2003) Hepatitis C virus infection in injection drug users in Bavaria: risk factors for seropositivity. Eur J Epidemiol 18:563–568
Bassani S, Toro C, de la Fuente L, Brugal MT, Jimenez V, Soriano V (2004) Rate of infection by blood-borne viruses in active heroin users in 3 Spanish cities. Medicina Clinica 122:570–572
Battjes RJ, Leukefeld CG, Pickens RW, Haverkos HW (1988) The acquired immunodeficiency syndrome and intravenous drug abuse. Bull Narc 40:21–34
Bayer BM, Daussin S, Hernandez M, Irvin L (1990) Morphine inhibition of lymphocyte activity is mediated by an opioid dependent mechanism. Neuropharmacology 29:369–374
Beld M, Penning M, Lukashov V, McMorrow M, Roos M, Pakker N, van den Hoek A, Goudsmit J (1998) Evidence that both HIV and HIV-induced immunodeficiency enhance HCV replication among HCV seroconverters. Virology 244:504–512
Bell J, Chan J, Kuk A (1995) Investigating the influence of treatment philosophy on outcome of methadone maintenance. Addiction 90:823–830
Benhamou Y, Bochet M, Di Martino V, Charlotte F, Azria F, Coutellier A, Vidaud M, Bricaire F, Opolon P, Katlama C, Poynard T (1999) Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. The Multivirc Group. Hepatology 30:1054–1058
Bidlack JM (2000) Detection and function of opioid receptors on cells from the immune system. Clin Diagn Lab Immunol 7:719–723
Blackard JT, Kang M, Sherman KE, Koziel MJ, Peters MG, Chung RT (2006) Effects of HCV treatment on cytokine expression during HCV/HIV coinfection. J Interferon Cytokine Res 26:834–838
Bobkov AF, Selimova LM, Khanina TA, Zverev SY, Pokrovsky VV, Weber JN, Bobkov EN, Rylkov AV (2005) Human immunodeficiency virus type 1 in illicit-drug solutions used intravenously retains infectivity. J Clin Microbiol 43:1937–1939
Bonacini M, Govindarajan S, Blatt LM, Schmid P, Conrad A, Lindsay KL (1999) Patients co-infected with human immunodeficiency virus and hepatitis C virus demonstrate higher levels of hepatic HCV RNA. J Viral Hepat 6:203–208
Bonkovsky HL, Tice AD, Yapp RG, Bodenheimer HC Jr, Monto A, Rossi SJ, Sulkowski MS (2008) Efficacy and safety of peginterferon alfa-2a/ribavirin in methadone maintenance patients: randomized comparison of direct observed therapy and self-administration. Am J Gastroenterol 103:2757–2765
Boschini A, Smacchia C, Di Fine M, Schiesari A, Ballarini P, Arlotti M, Gabrielli C, Castellani G, Genova M, Pantani P, Lepri AC, Rezza G (1996) Community-acquired pneumonia in a cohort of former injection drug users with and without human immunodeficiency virus infection: incidence, etiologies, and clinical aspects. Clin Infect Dis 23:107–113
Brenchley JM, Douek DC (2008a) HIV infection and the gastrointestinal immune system. Mucosal Immunol 1:23–30
Brenchley JM, Douek DC (2008b) The mucosal barrier and immune activation in HIV pathogenesis. Curr Opin HIV AIDS 3:356–361
Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH, Beilman GJ, Nguyen PL, Khoruts A, Larson M, Haase AT, Douek DC (2004) CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med 200:749–759
Brenchley JM, Price DA, Douek DC (2006a) HIV disease: fallout from a mucosal catastrophe? Nat Immunol 7:235–239
Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, Kazzaz Z, Bornstein E, Lambotte O, Altmann D, Blazar BR, Rodriguez B, Teixeira-Johnson L, Landay A, Martin JN, Hecht FM, Picker LJ, Lederman MM, Deeks SG, Douek DC (2006b) Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 12:1365–1371
Bruno R, Galastri S, Sacchi P, Cima S, Caligiuri A, DeFranco R, Milani S, Gessani S, Fantuzzi L, Liotta F, Frosali F, Antonucci G, Pinzani M, Marra F (2010) gp120 modulates the biology of human hepatic stellate cells: a link between HIV infection and liver fibrogenesis. Gut 59:513–520
Chamot E, de Saussure P, Hirschel B, Deglon JJ, Perrin LH (1992) Incidence of hepatitis C, hepatitis B and HIV infections among drug users in a methadone-maintenance programme. AIDS 6:430–431
Chao CC, Sharp BM, Pomeroy C, Filice GA, Peterson PK (1990) Lethality of morphine in mice infected with Toxoplasma gondii. J Pharmacol Exp Ther 252:605–609
Chao CC, Gekker G, Hu S, Sheng WS, Portoghese PS, Peterson PK (1995) Upregulation of HIV-1 expression in cocultures of chronically infected promonocytes and human brain cells by dynorphin. Biochem Pharmacol 50:715–722
Chetwynd J, Brunton C, Blank M, Plumridge E, Baldwin D (1995) Hepatitis C seroprevalence amongst injecting drug users attending a methadone programme. N Z Med J 108:364–366
Chisari FV (2005) Unscrambling hepatitis C virus-host interactions. Nature 436:930–932
Choi SH, Hwang SB (2006) Modulation of the transforming growth factor-beta signal transduction pathway by hepatitis C virus nonstructural 5A protein. J Biol Chem 281:7468–7478
Choi J, Ou JH (2006) Mechanisms of liver injury. III. Oxidative stress in the pathogenesis of hepatitis C virus. Am J Physiol Gastrointest Liver Physiol 290:G847–G851
Chuang LF, Killam KF Jr, Chuang RY (1993a) Increased replication of simian immunodeficiency virus in CEM x174 cells by morphine sulfate. Biochem Biophys Res Commun 195:1165–1173
Chuang RY, Blackbourne DJ, Chuang LF (1993b) Modulation of simian AIDS by opioids. Adv Biosci 86:573–583
Chuang RY, Chuang LF, Li Y, Kung HF, Killam KF Jr (1995) SIV mutations detected in morphine-treated Macaca mulatta following SIVmac239 infection. Adv Exp Med Biol 373:175–181
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
Chung RT, Andersen J, Volberding P, Robbins GK, Liu T, Sherman KE, Peters MG, Koziel MJ, Bhan AK, Alston B, Colquhoun D, Nevin T, Harb G, van der Horst C (2004) Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med 351:451–459
Cribier B, Rey D, Schmitt C, Lang JM, Kirn A, Stoll-Keller F (1995) High hepatitis C viraemia and impaired antibody response in patients coinfected with HIV. AIDS 9:1131–1136
Crofts N, Nigro L, Oman K, Stevenson E, Sherman J (1997) Methadone maintenance and hepatitis C virus infection among injecting drug users. Addiction 92:999–1005
Day C, Ross J, Dolan K (2003) Hepatitis C-related discrimination among heroin users in Sydney: drug user or hepatitis C discrimination? Drug Alcohol Rev 22:317–321
De Luca A, Bugarini R, Lepri AC, Puoti M, Girardi E, Antinori A, Poggio A, Pagano G, Tositti G, Cadeo G, Macor A, Toti M, D’Arminio Monforte A (2002) Coinfection with hepatitis viruses and outcome of initial antiretroviral regimens in previously naive HIV-infected subjects. Arch Intern Med 162:2125–2132
DeLeo JA, Tanga FY, Tawfik VL (2004) Neuroimmune activation and neuroinflammation in chronic pain and opioid tolerance/hyperalgesia. Neuroscientist 10:40–52
Diaz T, Des Jarlais DC, Vlahov D, Perlis TE, Edwards V, Friedman SR, Rockwell R, Hoover D, Williams IT, Monterroso ER (2001) Factors associated with prevalent hepatitis C: differences among young adult injection drug users in lower and upper Manhattan, New York City. Am J Public Health 91:23–30
Dole VP (1988) Implications of methadone maintenance for theories of narcotic addiction. Jama 260:3025–3029
Donahoe RM (1993) Neuroimmunomodulation by opiates: relationship to HIV infection and AIDS. Adv Neuroimmunol 3:31–46
Donahoe RM (2004) Multiple ways that drug abuse might influence AIDS progression: clues from a monkey model. J Neuroimmunol 147:28–32
Donahoe RM, Vlahov D (1998) Opiates as potential cofactors in progression of HIV-1 infections to AIDS. J Neuroimmunol 83:77–87
Donahoe RM, Byrd LD, McClure HM, Fultz P, Brantley M, Marsteller F, Ansari AA, Wenzel D, Aceto M (1993) Consequences of opiate-dependency in a monkey model of AIDS. Adv Exp Med Biol 335:21–28
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
Durante AJ, Selwyn PA, O’Connor PG (1998) Risk factors for and knowledge of Mycobacterium tuberculosis infection among drug users in substance abuse treatment. Addiction 93:1393–1401
Eisenstein TK, Rahim RT, Feng P, Thingalaya NK, Meissler JJ (2006) Effects of opioid tolerance and withdrawal on the immune system. J Neuroimmune Pharmacol 1:237–249
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
El-Hage N, Wu G, Wang J, Ambati J, Knapp PE, Reed JL, Bruce-Keller AJ, Hauser KF (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
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
El-Hage N, Podhaizer EM, Sturgill J, Hauser KF (2011) Toll-like receptor expression and activation in Astroglia: differential regulation by HIV-1 Tat, gp120, and morphine. Immunol Invest 40:498–522
El-Sharif A, Ashour HM (2008) Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) colonization and infection in intravenous and inhalational opiate drug abusers. Exp Biol Med (Maywood) 233:874–880
Eyster ME, Diamondstone LS, Lien JM, Ehmann WC, Quan S, Goedert JJ (1993) Natural history of hepatitis C virus infection in multitransfused hemophiliacs: effect of coinfection with human immunodeficiency virus. The Multicenter Hemophilia Cohort Study. J Acquir Immune Defic Syndr 6:602–610
Fecho K, Maslonek KA, Dykstra LA, Lysle DT (1996) Assessment of the involvement of central nervous system and peripheral opioid receptors in the immunomodulatory effects of acute morphine treatment in rats. J Pharmacol Exp Ther 276:626–636
Feng P, Meissler JJ Jr, Adler MW, Eisenstein TK (2005) Morphine withdrawal sensitizes mice to lipopolysaccharide: elevated TNF-alpha and nitric oxide with decreased IL-12. J Neuroimmunol 164:57–65
Feng P, Rahim RT, Cowan A, Liu-Chen LY, Peng X, Gaughan J, Meissler JJ Jr, Adler MW, Eisenstein TK (2006a) Effects of mu, kappa or delta opioids administered by pellet or pump on oral Salmonella infection and gastrointestinal transit. Eur J Pharmacol 534:250–257
Feng P, Truant AL, Meissler JJ Jr, Gaughan JP, Adler MW, Eisenstein TK (2006b) Morphine withdrawal lowers host defense to enteric bacteria: spontaneous sepsis and increased sensitivity to oral Salmonella enterica serovar Typhimurium infection. Infect Immun 74:5221–5226
Friedman H, Newton C, Klein TW (2003) Microbial infections, immunomodulation, and drugs of abuse. Clin Microbiol Rev 16:209–219
Garfein RS, Doherty MC, Monterroso ER, Thomas DL, Nelson KE, Vlahov D (1998) Prevalence and incidence of hepatitis C virus infection among young adult injection drug users. J Acquir Immune Defic Syndr Hum Retrovirol 18:S11–S19
Garten RJ, Lai S, Zhang J, Liu W, Chen J, Vlahov D, Yu XF (2004) Rapid transmission of hepatitis C virus among young injecting heroin users in Southern China. Int J Epidemiol 33:182–188
Ghany MG, Leissinger C, Lagier R, Sanchez-Pescador R, Lok AS (1996) Effect of human immunodeficiency virus infection on hepatitis C virus infection in hemophiliacs. Dig Dis Sci 41:1265–1272
Grossman Z, Meier-Schellersheim M, Paul WE, Picker LJ (2006) Pathogenesis of HIV infection: what the virus spares is as important as what it destroys. Nat Med 12:289–295
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
Gupta SK, Sellers E, Somoza E, Angles L, Kolz K, Cutler DL (2007) The effect of multiple doses of peginterferon alfa-2b on the steady-state pharmacokinetics of methadone in patients with chronic hepatitis C undergoing methadone maintenance therapy. J Clin Pharmacol 47:604–612
Han Y, Siliciano RF (2007) Keeping quiet: microRNAs in HIV-1 latency. Nat Med 13:1138–1140
Hariharan M, Scaria V, Pillai B, Brahmachari SK (2005) Targets for human encoded microRNAs in HIV genes. Biochem Biophys Res Commun 337:1214–1218
Hayashi N, Mita E (1999) Involvement of Fas system-mediated apoptosis in pathogenesis of viral hepatitis. J Viral Hepat 6:357–365
Haydon GH, Flegg PJ, Blair CS, Brettle RP, Burns SM, Hayes PC (1998) The impact of chronic hepatitis C virus infection on HIV disease and progression in intravenous drug users. Eur J Gastroenterol Hepatol 10:485–489
Hernandez MC, Flores LR, Bayer BM (1993) Immunosuppression by morphine is mediated by central pathways. J Pharmacol Exp Ther 267:1336–1341
Hilburger ME, Adler MW, Truant AL, Meissler JJ Jr, Satishchandran V, Rogers TJ, Eisenstein TK (1997) Morphine induces sepsis in mice. J Infect Dis 176:183–188
Hind CR (1990) Pulmonary complications of intravenous drug misuse. 2. Infective and HIV related complications. Thorax 45:957–961
Ho WZ, Guo CJ, Yuan CS, Douglas SD, Moss J (2003) Methylnaltrexone antagonizes opioid-mediated enhancement of HIV infection of human blood mononuclear phagocytes. J Pharmacol Exp Ther 307:1158–1162
Huang J, Wang F, Argyris E, Chen K, Liang Z, Tian H, Huang W, Squires K, Verlinghieri G, Zhang H (2007) Cellular microRNAs contribute to HIV-1 latency in resting primary CD4+ T lymphocytes. Nat Med 13:1241–1247
Hufert FT, Schmitz J, Schreiber M, Schmitz H, Racz P, von Laer DD (1993) Human Kupffer cells infected with HIV-1 in vivo. J Acquir Immune Defic Syndr 6:772–777
Hung CY, Lefkowitz SS, Geber WF (1973) Interferon inhibition by narcotic analgesics. Proc Soc Exp Biol Med 142:106–111
Jang JY, Shao RX, Lin W, Weinberg E, Chung WJ, Tsai WL, Zhao H, Goto K, Zhang L, Mendez-Navarro J, Jilg N, Peng LF, Brockman MA, Chung RT (2010) HIV infection increases HCV-induced hepatocyte apoptosis. J Hepatol 54:612–620
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
Koyuncuoglu H, Gungor M, Ang O, Inanc D, Ang-Kucuker M, Sagduyu H, Uysal V (1988) Aggravation by morphine and D-aspartic acid of pyelonephritis induced by i.v. inoculation of Staphylococcus aureus in rats. Infection 16:42–45
Kreek MJ (1992) Rationale for maintenance pharmacotherapy of opiate dependence. In: O’Brien CP, Jaffe JH (eds) Additive states. Raven, New York, pp 205–230
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
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
Laskus T, Radkowski M, Adair DM, Wilkinson J, Scheck AC, Rakela J (2005) Emerging evidence of hepatitis C virus neuroinvasion. AIDS 19:S140–S144
Lauer GM, Walker BD (2001) Hepatitis C virus infection. N Engl J Med 345:41–52
Lee HC, Lee NY, Chang CM, Chou CY, Wu YH, Wang LR, Ko NY, Liu CC, Ko WC (2007) Outbreak of Acinetobacter baumannii bacteremia related to contaminated morphine used for patient-controlled analgesia. Infect Control Hosp Epidemiol 28:1213–1217
Li Y, Wang X, Tian S, Guo CJ, Douglas SD, Ho WZ (2002) Methadone enhances human immunodeficiency virus infection of human immune cells. J Infect Dis 185:118–122
Li Y, Merrill JD, Mooney K, Song L, Wang X, Guo CJ, Savani RC, Metzger DS, Douglas SD, Ho WZ (2003a) Morphine enhances HIV infection of neonatal macrophages. Pediatr Res 54:282–288
Li Y, Zhang T, Douglas SD, Lai JP, Xiao WD, Pleasure DE, Ho WZ (2003b) Morphine enhances hepatitis C virus (HCV) replicon expression. Am J Pathol 163:1167–1175
Li Y, Ye L, Peng JS, Wang CQ, Luo GX, Zhang T, Wan Q, Ho WZ (2007) Morphine inhibits intrahepatic interferon- alpha expression and enhances complete hepatitis C virus replication. J Infect Dis 196:719–730
Lin W, Weinberg EM, Tai AW, Peng LF, Brockman MA, Kim KA, Kim SS, Borges CB, Shao RX, Chung RT (2008) HIV increases HCV replication in a TGF-beta1-dependent manner. Gastroenterology 134:803–811
Lin W, Tsai WL, Shao RX, Wu G, Peng LF, Barlow LL, Chung WJ, Zhang L, Zhao H, Jang JY, Chung RT (2010) Hepatitis C virus regulates transforming growth factor beta1 production through the generation of reactive oxygen species in a nuclear factor kappaB-dependent manner. Gastroenterology 138:2509–2518, 2518 e2501
Lin W, Wu G, Li S, Weinberg EM, Kumthip K, Peng LF, Mendez-Navarro J, Chen WC, Jilg N, Zhao H, Goto K, Zhang L, Brockman MA, Schuppan D, Chung RT (2011) HIV and HCV cooperatively promote hepatic fibrogenesis via induction of reactive oxygen species and NFkappaB. J Biol Chem 286:2665–2674
Litwin AH, Harris KA Jr, Nahvi S, Zamor PJ, Soloway IJ, Tenore PL, Kaswan D, Gourevitch MN, Arnsten JH (2009) Successful treatment of chronic hepatitis C with pegylated interferon in combination with ribavirin in a methadone maintenance treatment program. J Subst Abuse Treat 37:32–40
Llibre JM, Garcia E, Aloy A, Valls J (1993) Hepatitis C virus infection and progression of infection due to human immunodeficiency virus. Clin Infect Dis 16:182
Lockwood LL, Silbert LH, Fleshner M, Laudenslager ML, Watkins LR, Maier SF (1994) Morphine-induced decreases in in vivo antibody responses. Brain Behav Immun 8:24–36
Lucas GM, Griswold M, Gebo KA, Keruly J, Chaisson RE, Moore RD (2006) Illicit drug use and HIV-1 disease progression: a longitudinal study in the era of highly active antiretroviral therapy. Am J Epidemiol 163:412–420
Macias J, Japon MA, Saez C, Palacios RB, Mira JA, Garcia-Garcia JA, Merchante N, Vergara S, Lozano F, Gomez-Mateos J, Pineda JA (2005) Increased hepatocyte fas expression and apoptosis in HIV and hepatitis C virus coinfection. J Infect Dis 192:1566–1576
Mahajan SD, Schwartz SA, Shanahan TC, Chawda RP, Nair MP (2002) Morphine regulates gene expression of alpha- and beta-chemokines and their receptors on astroglial cells via the opioid mu receptor. J Immunol 169:3589–3599
Mahajan SD, Aalinkeel R, Reynolds JL, Nair BB, Fernandez SF, Schwartz SA, Nair MP (2005) Morphine exacerbates HIV-1 viral protein gp120 induced modulation of chemokine gene expression in U373 astrocytoma cells. Curr HIV Res 3:277–288
Martinez-Sierra C, Arizcorreta A, Diaz F, Roldan R, Martin-Herrera L, Perez-Guzman E, Giron-Gonzalez JA (2003) Progression of chronic hepatitis C to liver fibrosis and cirrhosis in patients coinfected with hepatitis C virus and human immunodeficiency virus. Clin Infect Dis 36:491–498
Mathei C, Buntinx F, van Damme P (2002) Seroprevalence of hepatitis C markers among intravenous drug users in western European countries: a systematic review. J Viral Hepat 9:157–173
Matthews-Greer JM, Caldito GC, Adley SD, Willis R, Mire AC, Jamison RM, McRae KL, King JW, Chang W-L (2001) Comparison of hepatitis C viral loads in patients with or without human immunodeficiency virus. Clin Diagn Lab Immunol 8:690–694
Mauss S, Berger F, Goelz J, Jacob B, Schmutz G (2004) A prospective controlled study of interferon-based therapy of chronic hepatitis C in patients on methadone maintenance. Hepatology 40:120–124
McCarthy JJ, Flynn N (2001) Hepatitis C in methadone maintenance patients: prevalence and public policy implications. J Addict Dis 20:19–31
McCarthy L, Wetzel M, Sliker JK, Eisenstein TK, Rogers TJ (2001) Opioids, opioid receptors, and the immune response. Drug Alcohol Depend 62:111–123
Mellon RD, Bayer BM (1998) Evidence for central opioid receptors in the immunomodulatory effects of morphine: review of potential mechanism(s) of action. J Neuroimmunol 83:19–28
Metzger DS, Woody GE, McLellan AT, O’Brien CP, Druley P, Navaline H, DePhilippis D, Stolley P, Abrutyn E (1993) Human immunodeficiency virus seroconversion among intravenous drug users in- and out-of-treatment: an 18-month prospective follow-up. J Acquir Immune Defic Syndr 6:1049–1056
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
Mohsen AH, Easterbrook PJ, Taylor C, Portmann B, Kulasegaram R, Murad S, Wiselka M, Norris S (2003) Impact of human immunodeficiency virus (HIV) infection on the progression of liver fibrosis in hepatitis C virus infected patients. Gut 52:1035–1040
Munshi N, Balasubramanian A, Koziel M, Ganju RK, Groopman JE (2003) Hepatitis C and human immunodeficiency virus envelope proteins cooperatively induce hepatocytic apoptosis via an innocent bystander mechanism. J Infect Dis 188:1192–1204
Nair MP, Schwartz SA, Polasani R, Hou J, Sweet A, Chadha KC (1997) Immunoregulatory effects of morphine on human lymphocytes. Clin Diagn Lab Immunol 4:127–132
Novick DM (2000) The impact of hepatitis C virus infection on methadone maintenance treatment. Mt Sinai J Med 67:437–443
Novick DM, Ochshorn M, Ghali V, Croxson TS, Mercer WD, Chiorazzi N, Kreek MJ (1989) Natural killer cell activity and lymphocyte subsets in parenteral heroin abusers and long-term methadone maintenance patients. J Pharmacol Exp Ther 250:606–610
Novick DM, Richman BL, Friedman JM, Friedman JE, Fried C, Wilson JP, Townley A, Kreek MJ (1993) The medical status of methadone maintenance patients in treatment for 11–18 years. Drug Alcohol Depend 33:235–245
Novick DM, Haverkos HW, Teller DW (1997) The medically ill substance abuser. In: Lowinson JM, Ruiz P, Milmam RB, Langrod JG (eds) Substance abuse: a comprehensive textbook. Williams and Wilkins, Baltimore, pp 534–550
Ochshorn M, Novick DM, Kreek MJ (1990) In vitro studies of the effect of methadone on natural killer cell activity. Isr J Med Sci 26:421–425
Peng X, Cebra JJ, Adler MW, Meissler JJ Jr, Cowan A, Feng P, Eisenstein TK (2001) Morphine inhibits mucosal antibody responses and TGF-beta mRNA in gut-associated lymphoid tissue following oral cholera toxin in mice. J Immunol 167:3677–3681
Perez-Olmeda M, Nunez M, Romero M, Gonzalez J, Castro A, Arribas JR, Pedreira J, Barreiro P, Garcia-Samaniego J, Martin-Carbonero L, Jimenez-Nacher I, Soriano V (2003) Pegylated IFN-alpha2b plus ribavirin as therapy for chronic hepatitis C in HIV-infected patients. AIDS 17:1023–1028
Perlman DC, Salomon N, Perkins MP, Yancovitz S, Paone D, Des Jarlais DC (1995) Tuberculosis in drug users. Clin Infect Dis 21:1253–1264
Peterson PK, Sharp B, Gekker G, Brummitt C, Keane WF (1987a) Opioid-mediated suppression of cultured peripheral blood mononuclear cell respiratory burst activity. J Immunol 138:3907–3912
Peterson PK, Sharp B, Gekker G, Brummitt C, Keane WF (1987b) Opioid-mediated suppression of interferon-gamma production by cultured peripheral blood mononuclear cells. J Clin Invest 80:824–831
Peterson PK, Gekker G, Brummitt C, Pentel P, Bullock M, Simpson M, Hitt J, Sharp B (1989) Suppression of human peripheral blood mononuclear cell function by methadone and morphine. J Infect Dis 159:480–487
Peterson PK, Sharp BM, Gekker G, Portoghese PS, Sannerud K, Balfour HH Jr (1990) Morphine promotes the growth of HIV-1 in human peripheral blood mononuclear cell cocultures. AIDS 4:869–873
Peterson PK, Gekker G, Schut R, Hu S, Balfour HH Jr, Chao CC (1993) Enhancement of HIV-1 replication by opiates and cocaine: the cytokine connection. Adv Exp Med Biol 335:181–188
Peterson PK, Gekker G, Hu S, Anderson WR, Kravitz F, Portoghese PS, Balfour HH Jr, Chao CC (1994) Morphine amplifies HIV-1 expression in chronically infected promonocytes cocultured with human brain cells. J Neuroimmunol 50:167–175
Peterson PK, Gekker G, Hu S, Sheng WS, Molitor TW, Chao CC (1995) Morphine stimulates phagocytosis of Mycobacterium tuberculosis by human microglial cells: involvement of a G protein-coupled opiate receptor. Adv Neuroimmunol 5:299–309
Peterson PK, Gekker G, Hu S, Lokensgard J, Portoghese PS, Chao CC (1999) Endomorphin-1 potentiates HIV-1 expression in human brain cell cultures: implication of an atypical mu-opioid receptor. Neuropharmacology 38:273–278
Peterson PK, Gekker G, Hu S, Cabral G, Lokensgard JR (2004) Cannabinoids and morphine differentially affect HIV-1 expression in CD4(+) lymphocyte and microglial cell cultures. J Neuroimmunol 147:123–126
Piccolo P, Borg L, Lin A, Melia D, Ho A, Kreek MJ (2002) Hepatitis C virus and human immunodeficiency virus-1 co-infection in former heroin addicts in methadone maintenance treatment. J Addict Dis 21:55–66
Piroth L, Duong M, Quantin C, Abrahamowicz M, Michardiere R, Aho LS, Grappin M, Buisson M, Waldner A, Portier H, Chavanet P (1998) Does hepatitis C virus co-infection accelerate clinical and immunological evolution of HIV-infected patients? AIDS 12:381–388
Pol S, Lamorthe B, Thi NT, Thiers V, Carnot F, Zylberberg H, Berthelot P, Brechot C, Nalpas B (1998) Retrospective analysis of the impact of HIV infection and alcohol use on chronic hepatitis C in a large cohort of drug users. J Hepatol 28:945–950
Poynard T, Yuen MF, Ratziu V, Lai CL (2003) Viral hepatitis C. Lancet 362:2095–2100
Quaglio G, Lugoboni F, Pajusco B, Sarti M, Talamini G, Lechi A, Mezzelani P, Des Jarlais DC (2003) Factors associated with hepatitis C virus infection in injection and noninjection drug users in Italy. Clin Infect Dis 37:33–40
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
Rahim RT, Meissler JJ, Zhang L, Adler MW, Rogers TJ, Eisenstein TK (2003) Withdrawal from morphine in mice suppresses splenic macrophage function, cytokine production, and costimulatory molecules. J Neuroimmunol 144:16–27
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
Reimer J, Schulte B, Castells X, Schafer I, Polywka S, Hedrich D, Wiessing L, Haasen C, Backmund M, Krausz M (2005) Guidelines for the treatment of hepatitis C virus infection in injection drug users: status quo in the European Union countries. Clin Infect Dis 40(Suppl 5):S373–S378
Reynolds JL, Mahajan SD, Sykes D, Nair MP (2006) Heroin-induces differential protein expression by normal human astrocytes (NHA). Am J Infect Dis 2:49–57
Risdahl JM, Khanna KV, Peterson PK, Molitor TW (1998) Opiates and infection. J Neuroimmunol 83:4–18
Rock RB, Gekker G, Hu S, Sheng WS, Cheeran M, Lokensgard JR, Peterson PK (2004) Role of microglia in central nervous system infections. Clin Microbiol Rev 17:942–964, table of contents
Rockstroh JK, Mocroft A, Soriano V, Tural C, Losso MH, Horban A, Kirk O, Phillips A, Ledergerber B, Lundgren J (2005) Influence of hepatitis C virus infection on HIV-1 disease progression and response to highly active antiretroviral therapy. J Infect Dis 192:992–1002
Rodriguez JW, Hunter R, Nair MP, Rios-Olivares E (2007) Increase T-regulatory cell number and expression of CXCR4 and mu-opioids on CD4+ T-cells by methadone is associated with enhancemment of HIV-1 infectivity. J Immunol 178: B17
Ronald PJ, Robertson JR, Elton RA (1994) Continued drug use and other cofactors for progression to AIDS among injecting drug users. AIDS 8:339–343
Rotman Y, Liang TJ (2009) Coinfection with hepatitis C virus and human immunodeficiency virus: virological, immunological, and clinical outcomes. J Virol 83:7366–7374
Roy S, Charboneau RG, Barke RA (1999) Morphine synergizes with lipopolysaccharide in a chronic endotoxemia model. J Neuroimmunol 95:107–114
Royer C, Steffan AM, Navas MC, Fuchs A, Jaeck D, Stoll-Keller F (2003) A study of susceptibility of primary human Kupffer cells to hepatitis C virus. J Hepatol 38:250–256
Schaefer M, Mauss S (2008) Hepatitis C treatment in patients with drug addiction: clinical management of interferon-alpha-associated psychiatric side effects. Curr Drug Abuse Rev 1:177–187
Schaefer M, Heinz A, Backmund M (2004) Treatment of chronic hepatitis C in patients with drug dependence: time to change the rules? Addiction 99:1167–1175
Schmitt MP, Gendrault JL, Schweitzer C, Steffan AM, Beyer C, Royer C, Jaeck D, Pasquali JL, Kirn A, Aubertin AM (1990) Permissivity of primary cultures of human Kupffer cells for HIV-1. AIDS Res Hum Retroviruses 6:987–991
Schulze-Krebs A, Preimel D, Popov Y, Bartenschlager R, Lohmann V, Pinzani M, Schuppan D (2005) Hepatitis C virus-replicating hepatocytes induce fibrogenic activation of hepatic stellate cells. Gastroenterology 129:246–258
Schweitzer C, Keller F, Schmitt MP, Jaeck D, Adloff M, Schmitt C, Royer C, Kirn A, Aubertin AM (1991) Morphine stimulates HIV replication in primary cultures of human Kupffer cells. Res Virol 142:189–195
Scott JD, McMahon BJ, Bruden D, Sullivan D, Homan C, Christensen C, Gretch DR (2006) High rate of spontaneous negativity for hepatitis C virus RNA after establishment of chronic infection in Alaska Natives. Clin Infect Dis 42:945–952
Selimova LM, Khanina TA, Kazennova EV, Zverev S, Pokrovskii VV, Bobkov AF (2002) Effect of heroin-containing substances on the infectivity of the human immunodeficiency virus type 1 in vitro. Vopr Virusol 47:16–20
Selvey LA, Denton M, Plant AJ (1997) Incidence and prevalence of hepatitis C among clients of a Brisbane methadone clinic: factors influencing hepatitis C serostatus. Aust N Z J Public Health 21:102–104
Selwyn PA, Budner NS, Wasserman WC, Arno PS (1993) Utilization of on-site primary care services by HIV-seropositive and seronegative drug users in a methadone maintenance program. Public Health Rep 108:492–500
Sherman KE, Rouster SD, Chung RT, Rajicic N (2002) Hepatitis C Virus prevalence among patients infected with Human Immunodeficiency Virus: a cross-sectional analysis of the US adult AIDS Clinical Trials Group. Clin Infect Dis 34:831–837
Sheth K, Bankey P (2001) The liver as an immune organ. Curr Opin Crit Care 7:99–104
Smyth BP, Barry J, Keenan E (2005) Irish injecting drug users and hepatitis C: the importance of the social context of injecting. Int J Epidemiol 34:166–172
Soto B, Sanchez-Quijano A, Rodrigo L, del Olmo JA, Garcia-Bengoechea M, Hernandez-Quero J, Rey C, Abad MA, Rodriguez M, Sales Gilabert M, Gonzalez F, Miron P, Caruz A, Relimpio F, Torronteras R, Leal M, Lissen E (1997) Human immunodeficiency virus infection modifies the natural history of chronic parenterally-acquired hepatitis C with an unusually rapid progression to cirrhosis. J Hepatol 26:1–5
Specter S (1994) Drugs of abuse and infectious diseases. J Fla Med Assoc 81:485–487
Squinto SP, Mondal D, Block AL, Prakash O (1990) Morphine-induced transactivation of HIV-1 LTR in human neuroblastoma cells. AIDS Res Hum Retroviruses 6:1163–1168
Staples CT Jr, Rimland D, Dudas D (1999) Hepatitis C in the HIV (human immunodeficiency virus) Atlanta V.A. (Veterans Affairs Medical Center) Cohort Study (HAVACS): the effect of coinfection on survival. Clin Infect Dis 29:150–154
Steele AD, Henderson EE, Rogers TJ (2003) Mu-opioid modulation of HIV-1 coreceptor expression and HIV-1 replication. Virology 309:99–107
Strain EC, Bigelow GE, Liebson IA, Stitzer ML (1999) Moderate- vs high-dose methadone in the treatment of opioid dependence: a randomized trial. Jama 281:1000–1005
Sulkowski MS, Thomas DL (2003) Hepatitis C in the HIV-Infected Person. Ann Intern Med 138:197–207
Sulkowski MS, Moore RD, Mehta SH, Chaisson RE, Thomas DL (2002) Hepatitis C and progression of HIV disease. JAMA 288:199–206
Sullivan LE, Moore BA, Chawarski MC, Pantalon MV, Barry D, O’Connor PG, Schottenfeld RS, Fiellin DA (2008) Buprenorphine/naloxone treatment in primary care is associated with decreased human immunodeficiency virus risk behaviors. J Subst Abuse Treat 35:87–92
Suzuki S, Chuang AJ, Chuang LF, Doi RH, Chuang RY (2002a) 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
Suzuki S, Chuang LF, Yau P, Doi RH, Chuang RY (2002b) Interactions of opioid and chemokine receptors: oligomerization of mu, kappa, and delta with CCR5 on immune cells. Exp Cell Res 280:192–200
Suzuki S, Carlos MP, Chuang LF, Torres JV, Doi RH, Chuang RY (2002c) Methadone induces CCR5 and promotes AIDS virus infection. FEBS Lett 519:173-177
Sylvestre DL, Clements BJ (2007) Adherence to hepatitis C treatment in recovering heroin users maintained on methadone. Eur J Gastroenterol Hepatol 19:741–747
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
Szabo I, Wetzel MA, Zhang N, Steele AD, Kaminsky DE, Chen C, Liu-Chen LY, Bednar F, Henderson EE, Howard OM, Oppenheim JJ, Rogers TJ (2003) Selective inactivation of CCR5 and decreased infectivity of R5 HIV-1 strains mediated by opioid-induced heterologous desensitization. J Leukoc Biol 74: 1074-82
Tenner-Racz K, Stellbrink HJ, van Lunzen J, Schneider C, Jacobs JP, Raschdorff B, Grosschupff G, Steinman RM, Racz P (1998) The unenlarged lymph nodes of HIV-1-infected, asymptomatic patients with high CD4 T cell counts are sites for virus replication and CD4 T cell proliferation. The impact of highly active antiretroviral therapy. J Exp Med 187:949–959
Thimme R, Oldach D, Chang KM, Steiger C, Ray SC, Chisari FV (2002) Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med 194:1395–1406
Thomas DL, Cannon RO, Shapiro CN, Hook EW 3rd, Alter MJ, Quinn TC (1994) Hepatitis C, hepatitis B, and human immunodeficiency virus infections among non-intravenous drug-using patients attending clinics for sexually transmitted diseases. J Infect Dis 169:990–995
Thomas DL, Vlahov D, Solomon L, Cohn S, Taylor E, Garfein R, Nelson KE (1995) Correlates of hepatitis C virus infections among injection drug users. [Review] [31 refs]. Medicine 74:212–220
Thomas DL, Shih JW, Alter HJ, Vlahov D, Cohn S, Hoover DR, Cheung L, Nelson KE (1996) Effect of human immunodeficiency virus on hepatitis C virus infection among injecting drug users. J Infect Dis 174:690–695
Torriani FJ, Rodriguez-Torres M, Rockstroh JK, Lissen E, Gonzalez-Garcia J, Lazzarin A, Carosi G, Sasadeusz J, Katlama C, Montaner J, Sette H Jr, Passe S, De Pamphilis J, Duff F, Schrenk UM, Dieterich DT (2004) Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 351:438–450
Tubaro E, Borelli G, Croce C, Cavallo G, Santiangeli C (1983) Effect of morphine on resistance to infection. J Infect Dis 148:656–666
Umbricht A, Hoover DR, Tucker MJ, Leslie JM, Chaisson RE, Preston KL (2003) Opioid detoxification with buprenorphine, clonidine, or methadone in hospitalized heroin-dependent patients with HIV infection. Drug Alcohol Depend 69:263–272
Verrando R, Robaeys G, Mathei C, Buntinx F (2005) Methadone and buprenorphine maintenance therapies for patients with hepatitis C virus infected after intravenous drug use. Acta Gastroenterol Belg 68:81–85
Wan Q, Wang X, Wang YJ, Song L, Wang SH, Ho WZ (2008) Morphine suppresses intracellular interferon-alpha expression in neuronal cells. J Neuroimmunol 199:1–9
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 J, Barke RA, Charboneau R, Loh HH, Roy S (2003) Morphine negatively regulates interferon-gamma promoter activity in activated murine T cells through two distinct cyclic AMP-dependent pathways. J Biol Chem 278:37622–37631
Wang CQ, Li Y, Douglas SD, Wang X, Metzger DS, Zhang T, Ho WZ (2005a) Morphine withdrawal enhances hepatitis C virus (HCV) replicon expression. Am J Pathol 167:1333–1340
Wang J, Barke RA, Charboneau R, Roy S (2005b) Morphine impairs host innate immune response and increases susceptibility to Streptococcus pneumoniae lung infection. J Immunol 174:426–434
Wang X, Tan N, Douglas SD, Zhang T, Wang YJ, Ho WZ (2005c) Morphine inhibits CD8+ T cell-mediated, noncytolytic, anti-HIV activity in latently infected immune cells. J Leukoc Biol 78:772–776
Wang X, Douglas SD, Peng JS, Zhou DJ, Wan Q, Ho WZ (2006) An in vitro model of morphine withdrawal manifests the enhancing effect on human immunodeficiency virus infection of human T lymphocytes through the induction of substance P. Am J Pathol 169:1663–1670
Wang J, Barke RA, Charboneau R, Schwendener R, Roy S (2008a) Morphine induces defects in early response of alveolar macrophages to Streptococcus pneumoniae by modulating TLR9-NF-kappa B signaling. J Immunol 180:3594–3600
Wang J, Barke RA, Ma J, Charboneau R, Roy S (2008b) Opiate abuse, innate immunity, and bacterial infectious diseases. Arch Immunol Ther Exp (Warsz) 56:299–309
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
Wang X, Ye L, Zhou Y, Liu MQ, Zhou DJ, Ho WZ (2011) Inhibition of anti-HIV microRNA expression: a mechanism for opioid-mediated enhancement of HIV infection of monocytes. Am J Pathol 178:41–47
Ye L, Wang X, Metzger DS, Riedel E, Montaner LJ, Ho W (2010) Upregulation of SOCS-3 and PIAS-3 impairs IL-12-mediated interferon-gamma response in CD56 T cells in HCV-infected heroin users. PLoS One 5:e9602
Yoon JH, Gores GJ (2002) Death receptor-mediated apoptosis and the liver. J Hepatol 37:400–410
Zanini B, Covolo L, Donato F, Lanzini A (2010) Effectiveness and tolerability of combination treatment of chronic hepatitis C in illicit drug users: meta-analysis of prospective studies. Clin Ther 32:2139–2159
Zaric GS, Barnett PG, Brandeau ML (2000) HIV transmission and the cost-effectiveness of methadone maintenance. Am J Public Health 90:1100–1111
Zhang T, Li Y, Ho WZ (2006) Drug abuse, innate immunity and hepatitis C virus. Rev Med Virol 16:311–327
Acknowledgements
Supported by the National Institutes of Health grants DA12815, DA27550, DA-25477, DA-22177, DA16022, and the grant A0901 from W.W.Smith Charitable Trust to Dr. Wen-Zhe Ho.
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The authors declare that there are no conflicts of interest.
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Xu Wang and Ting Zhang contributed equally to this work.
Source(s) of Support
The National Institutes of Health grants DA12815, DA27550, DA25477, DA-22177 and the grant A0901 from W.W.Smith Charitable Trust to Dr. Wen-Zhe Ho