U50488 inhibits HIV-1 expression in acutely infected monocyte-derived macrophages.
Opioids may play an immunomodulatory role in the pathogenesis of human immunodeficiency virus-1 (HIV-1) infection. Recently, synthetic kappa-opioid receptor (KOR) ligands have been found to have anti-human immunodeficiency virus type 1 activity in acutely infected brain macrophages. In the present study, we investigated whether the selective KOR ligand U50488 would exert such an anti-HIV-1 effect in acutely infected blood monocyte-derived macrophages (MDM). Treatment of acutely infected MDM with U50488 induced a concentration-dependent inhibition of HIV-1 expression. The dose--response relationship of U50488 was U-shaped with a peak effect observed at 10(-13) M, which was evident at both 7 and 14 days post-infection. The KOR antagonist nor-binaltorphimine blocked the anti-HIV-1 effect of U50488 by 73%, indicating involvement of a KOR-mediated mechanism. Also, expression of KOR mRNA and binding activity with a fluorescence-labeled KOR ligand supported the existence of KOR on MDM. Antibodies to the beta-chemokine, RANTES (regulated on activation normal T-cell expressed and secreted), but not to various other cytokines, blocked U50488 inhibition by 56% suggesting that the anti-HIV-1 effect of U50488 involved, in part, the production of RANTES by MDM. Taken together, these in vitro findings support the anti-HIV-1 property of U50488, and suggest that KOR ligands may have therapeutic potential for treating patients with acquired immunodeficiency syndrome.
Institute for Brain and Immune Disorders, Minneapolis Medical Research Foundation, Hennepin County Medical Center and the University of Minnesota Medical School, Minneapolis, MN 55404, USA.
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Chao
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Gekker
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Sheng
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Hu
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Peterson
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000008:administration & dosage / Q000494:pharmacology*; D000163:Acquired Immunodeficiency Syndrome / Q000378:metabolism*; D000208:Acute Disease; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000494:pharmacology*; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005453:Fluorescence; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000821:virology*; D009000:Monocytes / Q000187:drug effects* / Q000821:virology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018712:Analgesics, Non-Narcotic; D018946:Chemokine CCL5; D016207:Cytokines; D012333:RNA, Messenger; D017473:Receptors, Opioid, kappa; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer