title: A novel bivalent HIV-1 entry inhibitor reveals fundamental differences in CCR5-μ-opioid receptor interactions between human astroglia and microglia.
abstract: OBJECTIVE
  We explored whether the opiate, morphine, affects the actions of maraviroc, as well as a recently synthesized bivalent derivative of maraviroc linked to an opioid antagonist, naltrexone, on HIV-1 entry in primary human glia.
  
  
  METHODS
  HIV-1 entry was monitored in glia transiently transfected with an LTR construct containing a luciferase reporter gene under control of a promoter for the HIV-1 transactivator protein Tat. The effect of maraviroc and the bivalent ligand with or without morphine on CCR5 surface expression and cytokine release was also explored.
  
  
  RESULTS
  Maraviroc inhibits HIV-1 entry into glial cells, whereas morphine negates the effects of maraviroc leading to a significant increase in viral entry. We also demonstrate that the maraviroc-containing bivalent ligand better inhibits R5-tropic viral entry in astrocytes than microglia compared to maraviroc when coadministered with morphine. Importantly, the inhibitory effects of the bivalent compound in astrocytes were not compromised by morphine. Exposure to maraviroc decreased the release of pro-inflammatory cytokines and restricted HIV-1-dependent increases in CCR5 expression in both astrocytes and microglia, whereas exposure to the bivalent had a similar effect in astrocytes but not in microglia. The CCR5-μ-opioid receptor (MOR) stoichiometric ratio varied among the two cell types with CCR5 expressed at much higher levels than MOR in microglia, which could explain the effectiveness of the bivalent ligand in astrocytes compared to microglia.
  
  
  CONCLUSIONS
  A novel bivalent compound reveals fundamental differences in CCR5-MOR interactions and HIV-1 infectivity among glia, and has unique therapeutic potential in opiate abuse-HIV interactive comorbidity.
authors.affiliation: aDepartment of Pharmacology and Toxicology bDepartment of Medicinal Chemistry cInstitute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Nazira
authors.initials: N
authors.lastname: El-Hage
authors.forename: Seth M
authors.initials: SM
authors.lastname: Dever
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Podhaizer
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Arnatt
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Kurt F
authors.initials: KF
authors.lastname: Hauser
mesh_terms: D001253:Astrocytes / Q000187:drug effects / Q000821:virology*; D002478:Cells, Cultured; D003510:Cyclohexanes / Q000737:chemistry / Q000378:metabolism; D017930:Genes, Reporter; D023581:HIV Fusion Inhibitors / Q000737:chemistry / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008156:Luciferases / Q000032:analysis; D000077592:Maraviroc; D017628:Microglia / Q000187:drug effects / Q000821:virology*; D009271:Naltrexone / Q000737:chemistry / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism*; D011957:Receptors, Opioid / Q000378:metabolism*; D014230:Triazoles / Q000737:chemistry / Q000378:metabolism; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: C584933:CCR5 protein, human; D003510:Cyclohexanes; D023581:HIV Fusion Inhibitors; D019713:Receptors, CCR5; D011957:Receptors, Opioid; D014230:Triazoles; D009271:Naltrexone; D008156:Luciferases; D000077592:Maraviroc