title: Methylnaltrexone antagonizes opioid-mediated enhancement of HIV infection of human blood mononuclear phagocytes.
abstract: Opioid abuse has been postulated as a cofactor in the immunopathogenesis of human immunodeficiency virus (HIV) infection and AIDS. We and others have recently demonstrated that opioid enhances HIV infection of human macrophages through modulation of beta-chemokines and the CCR5 receptor and that this effect is reversed by naltrexone, a tertiary opioid antagonist. Tertiary opioid antagonists cannot be used in opioid-dependent patients because they precipitate withdrawal or reversal of analgesia. We determined whether the quaternary opioid antagonist methylnaltrexone (MNTX), now in phase III clinical trials for opioid-induced constipation, reverses the opioid-mediated enhancement of HIV infection of macrophages at clinically relevant doses. MNTX completely abrogated morphine-induced HIV Bal strain infection of macrophages. MNTX also inhibited the R5 strain (ADA) envelope-pseudotyped HIV replication induced by morphine. Furthermore, MNTX abolished morphine-mediated up-regulation of CCR5 receptor expression. The ability of MNTX to block opioid-induced CCR5 expression and HIV replication at clinically relevant doses may have additional benefit for opioid abusers with HIV infection, or patients with AIDS pain receiving opioids.
authors.affiliation: Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: Wen-Zhe
authors.initials: WZ
authors.lastname: Ho
authors.forename: Chang-Jiang
authors.initials: CJ
authors.lastname: Guo
authors.forename: Chun-Su
authors.initials: CS
authors.lastname: Yuan
authors.forename: Steven D
authors.initials: SD
authors.lastname: Douglas
authors.forename: Jonathan
authors.initials: J
authors.lastname: Moss
mesh_terms: D002478:Cells, Cultured; D015658:HIV Infections / Q000517:prevention & control*; D054303:HIV Reverse Transcriptase / Q000378:metabolism; D006801:Humans; D009000:Monocytes / Q000187:drug effects / Q000821:virology*; D009020:Morphine / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds; D019713:Receptors, CCR5 / Q000096:biosynthesis
chemical_list: D009292:Narcotic Antagonists; D009294:Narcotics; D000644:Quaternary Ammonium Compounds; D019713:Receptors, CCR5; C032257:methylnaltrexone; D009271:Naltrexone; D009020:Morphine; D054303:HIV Reverse Transcriptase