Methylnaltrexone antagonizes opioid-mediated enhancement of HIV infection of human blood mononuclear phagocytes.
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.
Ho
Wen-Zhe
WZ
Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Guo
Chang-Jiang
CJ
Yuan
Chun-Su
CS
Douglas
Steven D
SD
Moss
Jonathan
J
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
D009292:Narcotic Antagonists; D009294:Narcotics; D000644:Quaternary Ammonium Compounds; D019713:Receptors, CCR5; C032257:methylnaltrexone; D009271:Naltrexone; D009020:Morphine; D054303:HIV Reverse Transcriptase